Aryl glucoside derivative and use thereof in drug

ABSTRACT

A compound inhibiting a sodium-glucose cotransporter 1, and a pharmaceutically acceptable salt and a stereoisomer thereof. The compound is used in a pharmaceutical composition. Also disclosed are methods for preparing and using the pharmaceutical composition, and an application in preparing a drug and a composition of the compound for treating and improving diabetes, cardio-vascular diseases, weight reduction, fatty liver, astriction, and metabolism-related diseases, and cancer therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/CN2020/131253, filed on Nov. 24, 2020, which in turns claimspriority to Chinese Application No. 202010411247.8, filed May 15, 2020,the content of each application is hereby incorporated by reference inits entirety.

FIELD OF THE INVENTION

The present invention relates to a sodium-dependent glucose transporter1 (SGLT1) inhibitor, a method for synthesizing a drug containing acomposition thereof and use thereof in the treatment of metabolicdiseases, especially type 2 diabetes.

BACKGROUND OF THE INVENTION

Diabetes is a group of metabolic diseases characterized byhyperglycemia. Hyperglycemia is caused by defective insulin secretion,impaired biological action, or both. Long-term hyperglycemia in diabetescauses chronic damage and dysfunction of various tissues, especiallyeyes, kidneys, heart, blood vessels, and nerves. In 2012, the WorldHealth Organization reported that the incidence of diabetes in adultsover the age of 18 was greater than 9%. With the increase of population,aging and prolongation of life, the incidence of diabetes will increase.The incidence of diabetes is higher in obese people. Diabetes isprojected to become the seventh leading cause of death by 2030.

Sodium-dependent glucose transporter (SGLT) inhibitors can inhibit thereabsorption of glucose by the kidneys, allowing excess glucose to beexcreted from the urine, lowering blood glucose. It provides a new wayfor the treatment of diabetes and becomes a hot spot in the research ofhypoglycemic drugs. Over the past decades, new targeted drugs have beendeveloped for the treatment of diabetes. In recent years, successivelymarketed SGLT2 inhibitors have provided a new strategy for controllingblood glucose. The molecular structures of the successively marketeddrugs are as follows:

The SGLT family consists of several subtypes that play a role oftransporting carbohydrates across the cell membrane, during which theybind to sodium ion transporters. SGLT1 is mainly expressed in thegastrointestinal passage and is mainly responsible for the absorption ofglucose and galactose in the small intestine. SGLT1 is also present inthe proximal straight tubule of the kidney, where it contributes to thereabsorption of blood glucose. By inhibiting SGLT1, blood glucose can beprevented from being absorbed and used back to the blood, thus achievingthe goal of lowering blood glucose level.

Since SGLT1 inhibition may also provide an alternative therapy forglycemic control, the improvement of glycemic control by SGLT1inhibition is attractive because it can be independent of renalfunction. Current SGLT2-selective inhibitors are ineffective in patientswith moderate-to-severe renal impairment, which accounts forapproximately 30-40% of all diabetic patients. Inhibition of intestinalSGLT1 has potential efficacy in glycemic control. Through this action,the diabetes-related side effects of SGLT2 inhibitors, especiallygenital infections, can also be avoided.

Despite recent advances in the development of intestinal SGLT1inhibitors, there is still a need to develop new compounds with betterefficacy. Through continuous efforts, the present invention havedesigned compounds with the structure of general formula (V) and foundthat compounds with such structure showed excellent effects andfunctions, and in a larger scope, the relationship between structure andactivity efficacy have been revealed and clarified more deeply andcomprehensively, which has important application value.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (V), stereoisomer,tautomer or pharmaceutically acceptable salt thereof,

-   wherein, U, V, W and Q are each independently selected from nitrogen    atom or CH;

-   R_(1a), R_(1b), R_(1c) are each independently selected from halogen    or —OR_(1A), —NHR_(1A), wherein each R_(1A) is independently    hydrogen, C1-C6 alkyl or acyl;

-   R₂ is selected from —S(O)_(m)—R_(1A);

-   each of R₃, R₄, R₅, R_(6a), R_(7a), R_(6b), R_(7b) is independently    selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;

-   R_(A), R_(B) are each independently selected from hydrogen,    deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy,    halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, C2~C8    alkenyl, C2~C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,    —(CH₂)_(n1)R_(aa), —(CH₂)_(n1)OR_(aa), —SRaa, —(CH₂)_(n1)C(O)R_(aa),    —SRaa, —C(O)ORaa, —C(O)Raa, —S(O)_(m1)R_(aa),    —(CH₂)_(n1)S(O)_(m1)R_(aa), —NR_(aa)R_(bb), —C(O)NR_(aa)R_(bb),    —NR_(aa)C(O)R_(bb), —NR_(aa)S(O)_(m1)R_(bb);

-   alternatively R_(A), R_(B) together with the nitrogen atoms to which    they are attached form a 3- to 8-membered heterocycle, the    heterocycle may contain one or more carbon atoms, nitrogen atoms,    oxygen atoms or sulfur atoms, and may be further substituted by    halogen, alkyl, cycloalkyl, aryl, alkoxy, alkenyl, alkynyl, or oxo;

-   R_(aa), R_(bb) are each independently selected from hydrogen,    deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl,    haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl,    deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl,    aryl and heteroaryl, wherein said alkyl, deuterated alkyl,    haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl,    deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl,    aryl and heteroaryl are optionally further substituted by one or    more substituents selected from hydrogen, deuterium, silyl,    alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy,    substituted or unsubstituted amino, oxo, nitro, cyano, substituted    or unsubstituted alkenyl, substituted or unsubstituted alkynyl,    substituted or unsubstituted alkoxy, substituted or unsubstituted    hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted    or unsubstituted heterocyclyl, substituted or unsubstituted aryl and    substituted or unsubstituted heteroaryl;

-   Z is selected from oxygen atom, sulfur atom;

-   n1=0, 1, 2, 3, 4;

-   m1=0, 1, 2, 3, 4;

-   m = 0, 1, 2;

-   q=0, 1, 2, 3.

-   X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6    cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl;

-   Y is a linking group selected from the following structures:

-   

-   

-   

-   wherein, R_(E), R_(F), R_(G), R_(H) are each independently selected    from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;

-   E, J are selected from chemical bonds, —CH₂—, oxygen, —NH—;

-   s1=0, 1, 2, 3, 4, 5;

-   s2=0, 1, 2, 3, 4, 5;

-   s3=0, 1, 2, 3, 4, 5.

The present invention provides a compound of formula (VA), stereoisomer,tautomer or pharmaceutically acceptable salt thereof,

-   wherein, R_(1a), R_(1b), R_(1c) are each independently selected from    halogen or —OR_(1A), —NHR_(1A), wherein    -   R_(1A) is independently hydrogen, C1-C6 alkyl or acyl;

    -   R₂ is selected from —S(O)_(m)—R_(1A);

    -   each of R₃, R₄, R₅, R_(6b), R_(7b) is independently selected        from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;

    -   R_(A), R_(B) are each independently selected from hydrogen,        deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy,        haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano,        oxo, C2~C8 alkenyl, C2~C8 alkynyl, cycloalkyl, heterocyclyl,        aryl, heteroaryl, —(CH₂)_(n1)R_(aa), —(CH₂)_(n1)OR_(aa), —SRaa,        —(CH₂)_(n1)C(O)R_(aa), —SRaa, —C(O)ORaa, —C(O)Raa,        —S(O)_(m1)R_(aa), —(CH₂)_(n1)S(O)_(m1)R_(aa), —NR_(aa)R_(bb),        —C(O)NR_(aa)R_(bb), —NR_(aa)C(O)R_(bb), —NR_(aa)S(O)_(m1)R_(bb);

    -   alternatively R_(A), R_(B) together with the nitrogen atoms to        which they are attached form a 3- to 8-membered heterocycle, the        heterocycle may contain one or more carbon atoms, nitrogen        atoms, oxygen atoms or sulfur atoms, and may be further        substituted by halogen, alkyl, cycloalkyl, aryl, alkoxy,        alkenyl, alkynyl, or oxo;

    -   R_(aa), R_(bb) are each independently selected from hydrogen,        deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy,        hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino,        alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl,        cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said        alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl,        haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated        alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are        optionally further substituted by one or more substituents        selected from hydrogen, deuterium, silyl, alkylsilyl,        substituted or unsubstituted alkyl, halogen, hydroxy,        substituted or unsubstituted amino, oxo, nitro, cyano,        substituted or unsubstituted alkenyl, substituted or        unsubstituted alkynyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted hydroxyalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocyclyl, substituted or unsubstituted aryl and substituted        or unsubstituted heteroaryl;

    -   n1=0, 1, 2, 3, 4;

    -   m1=0, 1, 2, 3, 4;

    -   m = 0, 1, 2;

    -   q=0, 1, 2, 3;

    -   X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl,        C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

    -   Y is a linking group selected from the following structures:

    -   

    -   

    -   

    -   wherein, R_(E), R_(F), R_(G), R_(H) are each independently        selected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;

    -   E, J are selected from chemical bonds, —CH₂—, oxygen, —NH—;

    -   s1=0, 1, 2, 3, 4, 5;

    -   s2=0, 1, 2, 3, 4, 5;

    -   s3=0, 1, 2, 3, 4, 5.

The present invention provides a compound of formula (VA-1),stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

-   wherein, X is selected from hydrogen, deuterium, halogen, C1-C6    alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

-   R₅, R_(6b), R_(7b) are each independently selected from hydrogen,    deuterium, halogen, C1-C6 alkyl or acyl;

-   R_(A), R_(B) are each independently selected from hydrogen,    deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy,    halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, C2~C8    alkenyl, C2~C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,    —(CH₂)_(n1)R_(aa), —(CH₂)_(n1)OR_(aa), —SRaa, —(CH₂)_(n1)C(O)R_(aa),    —SRaa, —C(O)ORaa, —C(O)Raa, —S(O)_(m1)R_(aa),    —(CH₂)_(n1)S(O)_(m1)R_(aa), —NR_(aa)R_(bb), —C(O)NR_(aa)R_(bb),    —NR_(aa)C(O)R_(bb), —NR_(aa)S(O)_(m1)R_(bb);

-   R_(aa), R_(bb) are each independently selected from hydrogen,    deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl,    haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl,    deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl,    aryl and heteroaryl, wherein said alkyl, deuterated alkyl,    haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl,    deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl,    aryl and heteroaryl are optionally further substituted by one or    more substituents selected from hydrogen, deuterium, silyl,    alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy,    substituted or unsubstituted amino, oxo, nitro, cyano, substituted    or unsubstituted alkenyl, substituted or unsubstituted alkynyl,    substituted or unsubstituted alkoxy, substituted or unsubstituted    hydroxyalkyl, substituted or unsubstituted cycloalkyl, substituted    or unsubstituted heterocyclyl, substituted or unsubstituted aryl and    substituted or unsubstituted heteroaryl;

-   n1=0, 1, 2, 3, 4;

-   m1=0, 1, 2, 3, 4;

-   q=0, 1, 2, 3;

-   Y is a linking group selected from the following structures:

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

The present invention provides the following compounds, stereoisomers,tautomers or pharmaceutically acceptable salts thereof,

The present invention provides a compound of formula (VA-2),stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

-   wherein, X is selected from hydrogen, deuterium, halogen, C1-C6    alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

-   each of R₅, R_(6b), R_(7b) is independently selected from hydrogen,    deuterium, halogen, C1-C6 alkyl or acyl;

-   q=0, 1, 2, 3;

-   ring B has the following structure:

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   Y is a linking group selected from the following structures:

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

The present invention provides the following compounds, stereoisomers,tautomers or pharmaceutically acceptable salts thereof,

The present invention provides a compound of formula (I), stereoisomer,tautomer or pharmaceutically acceptable salt thereof,

-   wherein, R₁ is selected from F or —OR_(1A), —NHR_(1A), wherein    R_(1A) is independently hydrogen, C1-C6 alkyl or acyl;-   R₂ is selected from —S(O)_(m)—R_(1A), m = 0, 1, 2;-   each of R₃, R₄, R₅, R₆, R₇, R₈, R₉ is independently selected from    hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;-   m2=0, 1, 2, 3;-   n2=0, 1, 2, 3;-   X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6    cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;-   Y is a linking group, which is a linking arm composed of 2 to 17    carbon atoms, oxygen atoms, nitrogen atoms;-   Z is O, S or hydrogen.

The present invention provides a compound of formula (I-1),stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

-   wherein, R_(1a), R_(1b), R_(1c) are each independently selected from    F or —OR_(1A), —NHR_(1A), wherein R_(1A) is independently hydrogen,    C1-C6 alkyl or acyl;

-   R₂ is selected from —S(O)_(m)—R_(1A), m = 0, 1, 2;

-   each of R₃, R₄, R₅, R₆, R₇, R₈, R₉ is independently selected from    hydrogen, deuterium, halogen, C1-C6 alkyl, cycloalkyl,    cycloalkylalkyl or acyl, alkynylalkyl;

-   m2=0, 1, 2, 3;

-   n2=0, 1, 2, 3;

-   X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6    cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

-   Y1 is a linking group selected from the following structures:

-   

-   

-   

-   wherein, R_(E), R_(F), R_(G), R_(H) are each independently selected    from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;

-   E, J are selected from chemical bonds, —CH₂—, oxygen, —NH—;

-   s1=0, 1, 2, 3, 4, 5;

-   s2=0, 1, 2, 3, 4, 5;

-   s3=0, 1, 2, 3, 4, 5.

The present invention provides a compound of formula (I), including thecompound of the following structure of general formula (II),stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

-   wherein, X is selected from hydrogen, deuterium, halogen, C1-C6    alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;-   R₈, R₉ are selected from hydrogen, deuterium, halogen, C1 ~ C6 alkyl    or acyl groups;-   m2=0, 1, 2, 3;-   n2=1;-   Y is the linking group, which is a linking arm composed of 2 to 17    carbon atoms, oxygen atoms, nitrogen atoms.

The present invention provides a compound of formula (I), including thecompound of the following general structure (II-1), stereoisomer,tautomer or pharmaceutically acceptable salt thereof,

-   wherein, X is selected from hydrogen, deuterium, halogen, C1-C6    alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

-   R₈, R₉ are each independently selected from hydrogen, deuterium,    halogen, C1-C6 alkyl, cycloalkyl, cycloalkylalkyl or acyl,    alkynylalkyl;

-   m2=0, 1, 2, 3;

-   n2 = 1;

-   Y1 is a linking group selected from the following structures:

-   

-   

-   

-   wherein, R_(E), R_(F), R_(G), R_(H) are each independently selected    from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl;

-   E, J are selected from chemical bonds, —CH₂—, oxygen, —NH—;

-   s1=0, 1, 2, 3, 4, 5;

-   s2=0, 1, 2, 3, 4, 5;

-   s3=0, 1, 2, 3, 4, 5.

The present invention provides a compound of formula (II), including thecompound of the following structure of general formula (III),stereoisomer, tautomer or pharmaceutically acceptable salt thereof,

-   wherein, X is selected from hydrogen, deuterium, halogen, C1-C6    alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl;

-   R₈, R₉ are each independently selected from hydrogen, deuterium,    halogen, C1-C6 alkyl or acyl;

-   m2=0, 1, 2, 3;

-   n2 = 1;

-   Y₁ is a linking group selected from the following structures:

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

-   

The present invention provides the compound of formula (III), wherein Xis selected from hydrogen, deuterium, fluoro, bromo, iodo, methyl,ethyl, vinyl, and ethynyl.

The present invention provides the compound of formula (III), wherein R₉is selected from hydrogen, deuterium, fluoro, bromo, iodo, methyl,ethyl, C3-C8 cycloalkyl, vinyl, and ethynyl.

The present invention provides the following compounds, stereoisomers,tautomers or pharmaceutically acceptable salts thereof,

The present invention provides a pharmaceutical composition comprising atherapeutically effective dose of any one of the compounds of thepresent invention or a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier.

Any of the compounds described in the present invention orpharmaceutically acceptable salt thereof or the pharmaceuticalcomposition according to the present invention is used in the treatmentand improvement of diabetes, cardiovascular and cerebrovasculardiseases, weight loss, fatty liver, metabolism-related diseases and inthe treatment of tumors.

Any of the compounds described in the present invention orpharmaceutically acceptable salt thereof or the pharmaceuticalcomposition according to the present invention, as SGLT1/SGLT2inhibitor, is used in the preparation of medicines or pharmaceuticalcompositions for the treatment of diseases related to SGLT1/SGLT2function.

The use of the present invention, wherein the patient has taken or iscurrently taking other therapeutic drugs, including hypotensive drugs,hypolipidemic drugs, antidiabetic drugs, hypoglycemic drugs, weight-lossdrugs or appetite suppressants..

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 : Results of oral glucose tolerance test (OGTT) after 14 days ofcontinuous administration in rats;

FIG. 2 : Results of oral glucose tolerance test (OGTT) on day 6 after 5days of continuous administration in mice.

DETAILED DESCRIPTION OF THE INVENTION

As used above and elsewhere herein, the following terms andabbreviations have the meanings defined below. If not defined, alltechnical and scientific terms used in this specification have themeanings commonly understood by one of ordinary skill in the art.

The term “hydrogen” refers herein to —H.

The term “halogen” refers herein to —F, —Cl, —Br and —I.

The term “fluoro” refers herein to —F.

The term “chloro” refers herein to —Cl.

The term “bromo” refers herein to —Br.

The term “iodo” refers herein to —I.

The term “cyano” refers herein to —CN.

The term “amino” refers herein to —NH₂.

The term “hydroxyl” refers herein to —OH.

The term “nitro” refers herein to —NO₂.

The term “carboxy” refers herein to —COOH.

The term “nitroso” refers herein to —NO.

The term “linking arm” herein refers to a chemical structure with alinking function composed of 2 to 17 carbon atoms, oxygen atoms,nitrogen atoms. Specifically, it refers to an alkane structure with astraight or branched chain structure (including saturated alkane, alkeneand alkyne) or a similar alkane structure with a carbonyl group at oneend; wherein, under the premise of forming a stable chemical structure,any carbon atom may be replaced by oxygen atom, nitrogen atom, and mayalso be further substituted by a substituent group, wherein thesubstituent group includes: fluoro, chloro, bromo, iodo, cyano, nitro,hydroxyl, carboxyl, amino, alkyl, alkoxy, acyl, acylamino, ester group,amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,alkenyl, alkynyl and cycloalkoxy. The “linking arm” described hereininclude, but are not limited to, the following chemical structures:

The term “aryl” herein refers to a 6- to 10- membered all-carbonmonocyclic or fused polycyclic (i.e., ring that share adjacent pairs ofcarbon atoms) groups, polycyclic (i.e., ring with adjacent pairs ofcarbon atoms) group with a conjugated π electron system. Aryl groups maybe covalently attached to the defined chemical structure at any carbonatom that results in a stable structure. The aryl groups describedherein may be optionally substituted by one or more of the followingsubstituents: fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl,carboxyl, amino, alkyl, alkoxy, acyl, acylamino, ester group, amido,sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl,alkynyl and cycloalkoxy.

The term “heteroaryl” herein refers to an aromatic group composed of 5to 10 atoms and containing at least one heteroatom selected from N, O orS and the like. The term may be a single ring (non-limiting examplesinclude furan, thiophene, imidazole, pyrazole, pyridine, pyrazine,oxazole, thiazole, etc.) or multiple fused rings (non-limiting examplesinclude benzothiophene, benzofuran, indole, isoindole, etc.), whereinthe fused ring may or may not be an aromatic group containing aheteroatom, provided the linking point is through atoms of the aromaticheteroaryl group. The heteroaryl described herein may be optionallysubstituted by one or more of the following substituents: fluoro,chloro, bromo, iodo, cyano, nitro, hydroxy, amino, alkyl, alkoxy, acyl,acyloxy, acylamino, ester group, amido, sulfonyl, sulfinyl, cycloalkyl,cycloalkenyl, heterocycloalkyl, alkenyl, alkynyl and cycloalkoxy.

The term “cycloalkyl” herein refers to a cyclic alkyl group having 3 to10 carbon atoms, having a monocyclic or polycyclic ring (includingfused, bridged and spiro ring systems). Non-limiting examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like. The cycloalkyl groups described herein may beoptionally substituted by one or more of the following substituents:fluoro, chloro, bromo, iodo, cyano, nitro, hydroxy, carboxy, amino,alkyl, oxo, alkoxy, acyl, acyloxy, acylamino ester group, amido,cycloalkyl, cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy,alkynyl, cycloalkoxy, aryl or heteroaryl.

The term “heterocyclyl” refers to a substituted or unsubstituted,saturated or unsaturated aromatic ring, non-aromatic ring containing atleast 1 to 5 heteroatoms selected from N, O or S; the aromatic ring,non-aromatic ring may be 3- to 10-membered monocyclic ring, 4- to20-membered spiro ring, bicyclic ring or bridged ring, selectivelysubstituted N, S in the heterocyclyl ring may be oxidized to variousoxidation states. A 3- to 12-membered heterocycle is preferred.Non-limiting examples include oxiranyl, oxetanyl, oxolanyl, oxanyl,oxanyl, oxocanyl, aziridinyl, azetidinyl, azolidinyl, azacyclohexyl,azacyclopropenyl, 1,3-dioxocyclopentyl, 1,4-dioxocyclopentyl,1,3-dioxocyclopentyl, 1,3-dioxacyclohexyl, 1,3-dithiocyclohexyl,azacycloheptenyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl,pyrrolyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl,imidazolyl, piperidinyl, thiomorpholinyl, dihydropyranyl, thiadiazolyl,oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxacyclohexadienyl or the like.

The term “heterocycloalkyl” refers to a non-aromatic cycloalkyl groupcontaining at least one heteroatom selected from O, N and S andoptionally containing one or more double or triple bonds. Theheterocycloalkyl group as a whole may have 3 to 10 ring atoms. Theheterocycloalkyl group may be covalently attached to a defined chemicalstructure at any heteroatom or carbon atom that results in a stablestructure. Non-limiting examples of the heterocycloalkyl group include:pyrrolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl,tetrahydropyranyl, morpholinyl, pyranyl and the like. One or more N or Satoms on the heterocycloalkyl group may be oxidized (such as morpholineN-oxide, thiomorpholine S-oxide, thiomorpholine S,S-dioxide). Theheterocycloalkyl group may also contain one or more oxo groups such asphthalimido, piperidinone group, oxazolidinone group,2,4(1H,3H)-dioxo-pyrimidinyl, pyridine-2(1H)-keto group and the like.The heterocycloalkyl groups described herein may be optionallysubstituted by one or more of the following substituents: fluoro,chloro, bromo, iodo, cyano, nitro, hydroxy, carboxy, amino, alkyl,alkoxy, oxo, acyl, acyloxy, acylamino, ester group, amido, cycloalkyl,cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl,cycloalkoxy, aryl or heteroaryl.

The term “alkenyl” herein refers to an alkenyl group having 2 to 8carbon atoms and having at least one alkenyl unsaturated site.Non-limiting examples of the alkenyl groups include ethenyl, propenyl,allyl, isopropenyl, butenyl, isobutenyl, and the like. The alkenyl groupdescribed herein may be optionally substituted by one or more of thefollowing substituents: deuterium, fluoro, chloro, bromo, iodo, cyano,nitro, hydroxyl, carboxyl, amino, alkyl, alkoxyl, acyl, acylamino, estergroup, amido, sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, cycloalkoxy, mercapto, alkylmercapto, deuteratedalkylmercapto, sulphonyl, sulfoxide group, amino, silyl, phosphonyl,deuterated alkyl, heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl,arylalkyl, ester group.

The term “alkynyl” herein refers to an alkyl group in which two adjacentcarbon atoms are joined by a triple bond, wherein the alkyl group is asdefined herein. Alkynyl means an unsaturated alkyl group as definedabove composed of at least two carbon atoms and at least onecarbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-,2- or 3-butynyl, and the like. The alkynyl groups may be substituted orunsubstituted, and when substituted, the substituents are preferably oneor more of the following groups which are independently selected from:deuterium, fluoro, chloro, bromo, iodo, cyano, nitro, hydroxyl,carboxyl, amino, alkyl, alkoxyl, acyl, acylamino, ester group, amido,sulfonyl, sulfinyl, cycloalkyl, cycloalkenyl, heterocycloalkyl,cycloalkoxy, mercapto, alkylmercapto, deuterated alkylmercapto,sulphonyl, sulfoxide group, amino, silyl, phosphonyl, deuterated alkyl,heterocycloalkyl, aryl, heteroaryl, alkynyl, alkenyl, arylalkyl, estergroup.

The term “alkyl” herein refers to a saturated aliphatic hydrocarbylgroup having from 1 to 10 carbon atoms, and the term includes bothstraight chain and branched chain hydrocarbyl groups. Non-limitingexamples of the alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl,and the like. The alkyl groups described herein may be optionallysubstituted by one or more of the following substituents: fluoro,chloro, bromo, iodo, cyano, nitro, hydroxy, carboxyl, amino, alkyl,alkoxy, acyl, acyloxy, oxo, acylamino, ester group, amido, cycloalkyl,cycloalkenyl, heterocycloalkyl, alkenyl, alkenyloxy, alkynyl,cycloalkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aryl orheteroaryl.

The term “heteroalkyl” herein refers to an alkyl group that comprises atleast one heteroatom.

The term “alkoxy” herein refers to an alkyl group attached to theremainder of the molecule through an oxygen atom (—O—alkyl), wherein thealkyl group is as defined herein. Non-limiting examples of the alkoxygroups include methoxy, ethoxy, trifluoromethoxy, difluoromethoxy,n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentyloxy, and the like.

The term “acylamino” herein refers to —NR⁸—C(O)—alkyl,—NR⁸—C(O)—cycloalkyl, —NR⁸—C(O)—cycloalkenyl, —NR⁸—C(O)—aryl,—NR⁸—C(O)—heteroaryl and —NR⁸—C(O)—heterocycloalkyl, wherein R⁸ ishydrogen, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycloalkyland alkyl. Wherein, the groups such as hydrogen, cycloalkyl,cycloalkenyl, aryl, heteroaryl, heterocycloalkyl and alkyl are asdefined herein.

The term “acyl” herein refers to H—C(O)—, R⁹R¹⁰N—C(O)—, alkyl—C(O)—,cycloalkyl—C(O)—, cycloalkenyl—C(O)—, heterocycloalkyl—C(O)—, aryl—C(O)—and heteroaryl—C(O)—, wherein the R⁹ and R¹⁰ are each independentlyselected from hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl,heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl.Wherein, the groups such as hydrogen, hydroxy, alkyl, heterocycloalkyl,aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkylare as defined herein.

The term “oxo” refers to the description of the oxidation state ofcarbon atoms, nitrogen atoms, sulfur atoms, and the like by oxygenatoms, the representative structures formed after the oxidation ofcarbon atoms, nitrogen atoms, sulfur atoms, and the like by oxygen atomsinclude but are not limited to functional groups such as hydroxyl,alkoxy, carbonyl, oxynitride, sulfoxide, and sulphone.

The term “sulfonyl” herein refers to R¹¹R¹²N—S(O)₂—, cycloalkyl—S(O)₂—,cycloalkenyl—S(O)₂—, arylS(O)₂—, heteroaryl—S(O)₂—,heterocycloalkyl—S(O)₂— and alkyl—S(O)₂—, wherein the R¹¹ and R¹² areeach independently selected from hydrogen, hydroxyl, alkyl,heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl, cycloalkenyl,acyl or cycloalkyl. Wherein, the groups such as hydrogen, hydroxy,alkyl, heterocycloalkyl, aryl, heteroaryl, sulfonyl, sulfinyl,cycloalkenyl, acyl and cycloalkyl are as defined herein.

The term “sulfinyl” herein refers to R¹³R¹⁴N—S(O)—, cycloalkyl—S(O)—,cycloalkenyl—S(O)—, arylS(O)—, heteroaryl—S(O)—, heterocycloalkyl—S(O)—or alkyl—S(O)—, wherein the R¹³ and R¹⁴ are each independently selectedfrom hydrogen, hydroxyl, alkyl, heterocycloalkyl, aryl, heteroaryl,sulfonyl, sulfinyl, cycloalkenyl, acyl or cycloalkyl. Wherein, thegroups such as hydrogen, hydroxy, alkyl, heterocycloalkyl, aryl,heteroaryl, sulfonyl, sulfinyl, cycloalkenyl, acyl and cycloalkyl are asdefined herein.

The term “acyloxy” herein refers to —O—C(O)—alkyl, —O—C(O)—cycloalkyl,—O—C(O)—cycloalkenyl, —O—C(O)—aryl, —O—C(O)—heteroaryl and—O—C(O)—heterocycloalkyl, wherein the groups such as alkyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are as definedherein.

The term “ester group” herein refers to alkyl—O—C(O)—,cycloalkyl—O—C(O)—, cycloalkenyl—O—C(O)—, heterocycloalkyl—O—C(O)—,aryl—O—C(O)— and heteroaryl—O—C(O)—, wherein the groups such as alkyl,cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl are asdefined herein.

The term “optional” or “optionally” means that the subsequentlydescribed event or circumstance may, but does not necessarily, occur,and this description includes cases in which the event or circumstanceoccurs and does not occur.

The term “optionally substituted by...” means that the structure isunsubstituted or substituted by one or more substituents described inthe present invention. The term “substitution” herein means the singleor multiple substitution of any group by a designated substituent to theextent that such single or multiple substitution (including multiplesubstitutions in the same moiety) is chemically permissible, whereineach substituent can be located at any available position on the groupand can be attached through any available atom on the substituent. “Anyavailable position” refers to any position on the group, which ischemically obtainable by methods known in the art or as taught hereinand does not create molecules that are excessively unstable. When thereare two or more substituents on any group, each substituent is definedindependently of any other substituent and thus may be the same ordifferent.

In various parts of the specification, substituents of the compounds ofthe present invention are disclosed in the form of groups or ranges.This specifically means that the present invention encompasses each ofthe members of such groups or ranges or subgroups of each of themembers. The term “C₁₋₆ alkyl” specifically means that methyl, ethyl, C₃alkyl, C₄ alkyl, C₅ alkyl and C₆ alkyl are disclosed separately.

The term “compounds of the present invention” (unless otherwisespecifically indicated) herein refers to compounds of formula (I) andformula (II) and all pure and mixed stereoisomers, geometric isomers,tautomers, solvates, prodrugs and isotopically labeled compounds and anypharmaceutically acceptable salts thereof. The solvate of the compoundof the present invention means a compound or a salt thereof combinedwith a stoichiometric and non-stoichiometric solvent, such as a hydrate,an ethylate, a methylate, an acetonate or the like. The compound mayalso be present in one or more crystalline states, i.e., as aco-crystal, a polymorph, or it may be present as an amorphous solid. Allsuch forms are covered by the claims.

The term “pharmaceutically acceptable” means that the substance orcomposition must be chemically and/or toxicologically compatible withthe other ingredients that make up the formulation and/or the mammaltreated by it.

The term “stereoisomer” herein refers to compounds with different chiralproperties having one or more stereocenters, including the enantiomersand diastereomers.

The term “tautomer” herein refers to structural isomers with differentenergies that can cross the low energy barrier and thus convert to eachother. One example is proton tautomers including tautomers thatinterconvert by proton transfer, such as enol-keto tautomers andimine-enamine tautomers, or a tautomeric form of a heteroaryl groupcontaining a ring atom attached to ring-NH-moiety and ring=N-moiety,such as pyrazole, imidazole, benzimidazole, triazole and tetrazole.Valence tautomers include those in which some bonding electronsrecombine to interconvert..

The term “prodrug” herein refers to any derivative of the compound ofthe present invention that, when administered to a subject, directly orindirectly provides the compound of the present invention, an activemetabolite or residue thereof. Especially preferred are thosederivatives or prodrugs that increase the bioavailability, metabolicstability and tissue targeting of the compounds of the presentinvention.

The compounds of the present invention may be used in the form of salts,such as “pharmaceutically acceptable salts” derived from inorganic ororganic acids. These include, but are not limited to, the followingsubstances: acetate, adipate, alginate, citrate, aspartate, benzoate,besylate, ethanesulfonate, disulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentane propionate, lauryl sulfate,ethanesulfonate, glucoheptonate, glycerophosphate, hemisulphate,heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, ethanesulfonate, hydrochloride, 2-naphthalenesulfonate, oxalate, pectate, sulfate, 3-phenylpropionate, picrate,trimethylacetate, propionate, succinate, tartrate, thiocyanate,p-toluenesulfonate and decanoate. In addition, basic nitrogen-containinggroups can be quaternized with the following reagents to form quaternaryammonium salts: such as lower alkyl halide, including chloride, bromideand iodide of methyl, ethyl, propyl and butyl groups; such asdialkylsulfate, including dimethylsulfate, diethylsulfate,dibutylsulfate and dipentylsulfate; such as long chain halide, includingchloride, bromide and iodide of decyl, lauryl, myristyl, and stearyl;such as aralkyl halide, such as bromide of benzyl and phenethyl, and thelike.

The present invention also includes isotopically labeled compounds ofthe present invention, which are identical to those disclosed above instructure, but in which one or more atoms are replaced by an atom havingthe same number of protons but a different number of neutrons. Examplesof the isotope incorporating into the compounds of the present inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur,fluorine, chlorine and iodine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O,³⁵S, ¹⁸F, ³⁶Cl and ¹³¹I, etc.

The compounds of the present invention, stereoisomers, tautomers orpharmaceutically acceptable salts thereof, and the compounds of theabove forms containing the above isotopes and/or isotopes of other atomsare all within the scope of the present invention. Certain isotopicallylabeled compounds of the present invention, such as those labeled with³H or ¹⁴C, can be used in drug tissue distribution assays, andtherefore, these ³H or ¹⁴C isotopes are particularly preferred becauseof their ease of preparation and detection. In addition, certaincompounds of the present invention replaced by heavier isotopes such as²H have certain therapeutic advantages due to better metabolicstability, such as increased in vivo half-life and lower doses, etc.,therefore, ²H is also preferred in some cases.

EXAMPLES

The following examples are used to further illustrate the presentinvention, but the present invention is not limited thereto. Throughoutthe present application, various examples of the compounds and methodsof the present invention are referred herein. The various examplesdescribed are intended to provide a number of illustrative examples andshould not be construed as a description of alternatives. At the sametime, it should be noted that the examples (including various methodsand parameters) discussed herein are merely intended to illustrate theinvention and do not limit the scope of protection of the invention byany means. For the purpose of describing the present invention, specificexamples are set forth below. However, it is to be understood that thepresent invention is not limited to these examples, and the followingexamples are merely intended to provide a method of practicing thepresent invention and do not limit the scope of the present invention byany means.

The preparation method of the compound of formula (I) in any item of thepresent invention, stereoisomer, tautomer or pharmaceutically acceptablesalt thereof, comprises the following steps, Scheme 1:

SM1-1 and SM2-1 are reacted under certain chemical reaction conditionsto prepare the compound of general formula (I), wherein each substituentis defined as before;

-   Scheme 2:

-   

-   SM1-2 and SM2-2 are reacted under certain chemical reaction    conditions to prepare the compound of general formula (I), wherein    each substituent is defined as before;

The compounds provided by the present invention can be prepared bystandard synthetic methods well known in the art, and this specificationprovides general methods for preparing the compounds of the presentinvention. The starting materials are usually commercially available,for example, purchased from companies such as Alfa Aesar®,Sigma-Aldrich®, TCI, J&K®, Shaoyuan Chemical, Energy Chemical, etc., orprepared by methods well known to those skilled in the art.

The compounds of the present invention and the corresponding preparationmethods are further explained and listed below by means of examples andpreparations. It should be understood that although typical or preferredreaction conditions (such as reaction temperature, time, molar ratio ofreactants, reaction solvent and pressure, etc.) are given in thespecific examples, other reaction conditions may also be used by thoseskilled in the art. Optimal reaction conditions may vary with theparticular reaction substrates or solvents used, but such conditions canbe determined by one skilled in the art through routine optimization.

The structures of the compounds in the following examples werecharacterized by nuclear magnetic resonance (NMR) and/or massspectrometry (MS). NMR spectrometer was used, the compound was dissolvedin appropriate deuterated reagents and analyzed by ¹H-NMR at ambienttemperature with TMS as an internal standard. NMR chemical shifts (δ)were measured in ppm and the following abbreviations were used: s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; brs, broadsinglet. MS was determined by mass spectrometer (ESI).

The starting materials of the reaction, intermediates and the compoundsof examples can be separated and purified by conventional techniquessuch as precipitation, filtration, crystallization, evaporation,distillation and chromatography (such as column chromatography, TLCseparation and purification, etc.) and the like.

HSGF254 thin layer chromatography silica gel plate (0.2±0.03 mm) wasused for TLC, and HSGF254 thin layer chromatography thick preparationplate (0.9 ~ 1 mm) was used for TLC separation and purification. 300-400mesh silica gel was used as the carrier for column chromatography.

Commercial solvents and reagents used in the test, unless otherwisespecified, can be used directly without further purification ortreatment after purchase. When referring to other examples or syntheticmethods, the reaction conditions (reaction temperature, reactionsolvent, molar ratio of reactants or/and reaction duration) may bedifferent. In general, the progress of the reaction can be monitored byTLC, and the appropriate time can be selected to terminate the reactionand carry out post-treatment accordingly. The purification conditions ofthe compounds may also vary, in general, an appropriate columnchromatography eluent is selected according to the R_(f) value of TLC,or the corresponding compounds are separated and purified by preparativeTLC.

Preparation of the Intermediates Intermediate:4-(4-(2-methyl-5-(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyricAcid

5-Bromo-N-methoxy-N,2-dimethylbenzamide

5-Bromomethylbenzoic acid (24.0 g) and dichloromethane (600 ml) wereadded into a 1-liter reaction flask, and dimethyl sulfoxide (16.2 ml),N,N-dimethylformamide (3.6 ml) were added dropwise successively, themixture was returned to room temperature and stirred for 3 h afterdropping. The reaction solution was concentrated to dryness,dichloromethane (190 ml), N,O-dimethylhydroxylamine hydrochloride (31.0g) were added successively, the temperature was cooled to 0° C. in anice bath, triethylamine (46.5 ml) was added dropwise. After addition,the solution was returned to room temperature and stirred for 15 h. Thereaction solution was poured into 1 M diluted hydrochloric acid, liquidseparation was carried out, the aqueous phase was extracted twice withdichloromethane, the organic phases were combined, washed with saturatedsalt solution, dried on anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The concentrate was purified bycolumn chromatography to obtain 23.1 g of colorless liquid.

Bromo-2-methylphenyl)(4-chlorophenyl)methanone

The product of the previous step (18.7 g) and tetrahydrofuran (150 ml)were added into a 500 ml reaction flask, cooled to 0° C.,4-chlorophenylmagnesium bromide (1 M in Et₂O) was added dropwise, andthe mixture was stirred at room temperature for 2 h after dropping. Thereaction solution was poured into saturated aqueous ammonium chloridesolution, extracted with ethyl acetate for three times, the organicphases were combined, washed with saturated salt solution, dried onanhydrous sodium sulfate, filtered, concentrated under reduced pressure,and purified by column chromatography to obtain 18.0 g of white solid.¹H NMR(400 MHz,CDCl₃):δ7.76(m,2H), 7.54(dd,J=2.1,8.2 Hz,1H), 7.48(m,2H),7.43(d,J=2.1 Hz,1H), 7.20(d,J=8.2 Hz, 1H),2.27(s,1H).

4-Bromo(4-chlorobenzyl)-1-toluene

Bromo-2-methylphenyl)(4-chlorophenyl)methanone (23.0 g), acetonitrile(230 ml) and triethylsilane (52.9 ml, 331.2 mmol) were added into a 500ml reaction flask, cooled to 0° C., boron trifluoride ether (54.6 ml)was slowly added dropwise, kept stirring at 0° C. for 30 min afteraddition, and then the mixture was heated to 65° C. and stirred for 2 h.After the reaction was completed, the reaction solution was cooled to 0°C., and saturated aqueous sodium bicarbonate solution was slowly addeduntil no bubbles were generated, extracted with ethyl acetate for threetimes, the organic phases were combined, washed with saturated saltsolution, dried on anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure, and purified by column chromatography (elutingwith petroleum ether) to obtain 18.5 g of white solid.

(4-Chlorobenzyl)-4-methylphenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone

(3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholinyl)methanone (14.3 g) and tetrahydrofuran(150 ml) were added into a 500 ml reaction flask, cooled to 0° C.,tert-butylmagnesium chloride (1 M in THF, 57.5 ml, 57.5 mmol) was addeddropwise, after addition, the mixture was continued to stir for 30 min.

4-Bromo(4-chlorobenzyl)-1-toluene (18.5 g) and tetrahydrofuran (180 ml)were added into a 1L reaction flask under nitrogen protection, cooled to-78° C., n-butyllithium (1.6 M in hexane) was slowly added dropwise andstirred for 10 min. Then, the newly prepared Grignard reaction solutionabove was added, and after addition, the mixture was returned to roomtemperature and continued to stir for 1 h. After the reaction wascompleted, the reaction solution was poured into saturated aqueousammonium chloride solution, extracted with ethyl acetate for threetimes, the organic phases were combined, washed with saturated saltsolution, dried on anhydrous sodium sulfate, filtered, concentratedunder reduced pressure, and purified by column chromatography to obtain14.2 g of white solid. ¹H NMR(400 MHz,CDCl₃):δ7.90-7.88(dd,J=1.8,7.9Hz,1H), 7.77(d,J=1.6 Hz,1H),7.32-7.30(d,J=8.0Hz,1H),7.28-7.26(m,2H),7.08-7.06(d,J=8.4 Hz,2H), 6.10(d,J 3.6Hz,1H),5.31(d,J 2.7 Hz,1H),4.61(d,J 3.6Hz,1H),4.58(s,1H),4.02(s,2H),3.09(s,1H),2.31(s,3H),1.57(s,3H),1.38(s,3H).

(3aS,5S,6R,6aS)-5-((s)-(3-(4-chlorobenzyl)-4-methylphenyl)(hydroxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol

(3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholinyl)methanone(14.2 g), cerium chloride heptahydrate (15.7 g) and methanol (280 ml)were added into a 500 ml reaction flask, cooled to 0° C. in an ice bath,and a solution (16 ml) of sodium borohydride (1.6 g) in 1 M aqueoussodium hydroxide was slowly added dropwise. After addition, the mixturewas returned to room temperature and stirred for 1 h. The reactionsolution was poured into saturated aqueous ammonium chloride solution,extracted with ethyl acetate for three times, the organic phases werecombined, washed with saturated salt solution, dried on anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to obtain13.0 g of pale yellow solid, which was directly used in the nextreaction.

(3S,4R,5S,6S)-6-(3-(4-Chlorobenzyl)-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate

(3aS,5S,6R,6aS)-5-((s)-(3-(4-chlorobenzyl)-4-methylphenyl)(hydroxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(13.0 g), glacial acetic acid (65 ml) and water (65 ml) were added intoa 500 ml reaction flask, heated to 110° C. and stirred for 4 h. Thereaction solution was concentrated to dryness, azeotropically distilledwith toluene for three times, the residue was dissolved in 130 ml ofacetonitrile, triethylamine (44.5 ml) was added, and a solution (65 ml)of acetic anhydride (30.1 ml) in acetonitrile was slowly added dropwiseat 35° C. under nitrogen protection. After addition, the mixture wascooled to room temperature naturally and stirred for 15 h. The reactionsolution was diluted with ethyl acetate, water was added, and liquidseparation was carried out. The aqueous phase was extracted with ethylacetate for three times. The organic phases were combined, washed oncewith diluted hydrochloric acid and saturated salt solution in turn,dried on anhydrous sodium sulfate, filtered, and concentrated underreduced pressure, purified by column chromatography to obtain 14.6 g ofyellow solid. ¹H NMR(400MHz,CDCl₃):δ7.26-7.23(m,2H),7.19-7.14(m,2H),7.09(s,1H),7.01(d,J=8.5Hz,2H), 5.88( d,J=8.2 Hz, IH),5.37(t,J=9.5 Hz, IH),5.28(t,J=8.9 Hz,IH),5.20(t,J=9.6 Hz, IH),4.50( d,J=9.9 Hz, 1H),3.98-3.90(m,2H),2.18(s,3H),2.12(s,3H),2.08(s,3H),2.03(s,3H), 1.78(s,3H).

(2S,3S,4R,5S,6R)-2-(3-(4-Chlorobenzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate

(3S,4R,5S,6S)-6-(3-(4-Chlorobenzyl)-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate (14.6 g), thiourea (4.2 g), 1,4-dioxane (150 ml),trimethylsilyl trifluoromethanesulfonate (9.9 ml) were added into a 500ml reaction flask, heated to 90° C. and stirred for 2 h. After thereaction was completed, the solution was cooled to room temperature,iodomethane (5.1 ml) and N,N-diisopropylethylamine (27.1 ml) were addedsuccessively, and the mixture was stirred at room temperature for 15 h.Ethyl acetate and water were added, stirred, and liquid separation wascarried out. The aqueous phase was extracted with ethyl acetate forthree times, the organic phases were combined, washed once with dilutedhydrochloric acid and saturated salt solution in turn, dried onanhydrous sodium sulfate, filtered, and concentrated under reducedpressure, purified by column chromatography to obtain 11.4 g of paleyellow solid. ¹H NMR (400MHz,CDCl₃):67.26-7.23(m,2H),7.18-7.14(m,2H),7.06(s, 1H),7.03-7.00(m,2H),5.35(t,J=9.4 Hz,1H),5.23(t,J=9.6 Hz, IH),5.13(t,J=9.7Hz, IH),4.53(d,J=9.9 Hz, 1H),4.4 0(d,J=9.8 Hz,1H),3.99-3.88(m,2H),2.20(s,3H),2.19(s,3H),2.11(s,3H),2.03(s,3H),1.78(s,3H).

(25,3S,4R,5S,6R)-2-(3-(4-((E)-4-methoxy-4-oxobut-1-en-1-yl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate

(2S,3S,4R,5S,6R)-2-(3-(4-chlorobenzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate (1.0 g), methyl 3-butenoate (1.0 ml), Pd₂(dba)₃ (366 mg),tri-tert-butylphosphine tetrafluoroborate (232 mg),dicyclohexylmethylamine (1.2 ml) and N-methylpyrrolidone (10 ml) wereadded into a 25 ml microwave reaction tube, after nitrogen replacement,the mixture was heated to 160° C. by microwave and reacted for 1 h. Thisoperation process was repeated for 10 times and for a total of 10 g ofraw materials. The reaction solutions were combined and diluted withethyl acetate, water was added, and liquid separation was carried out.The aqueous phase was extracted with ethyl acetate for three times, theorganic phases were combined, washed once with diluted hydrochloric acidand saturated salt solution in turn, dried on anhydrous sodium sulfate,filtered, and concentrated under reduced pressure, purified by columnchromatography to obtain 6.4 g of pale yellow solid. ¹H NMR(400MHz,CDCl₃):δ7.30-7.28(m,2H),7.16-7.15(m,2H),7.04-7.02(m,3H),6.47(d,J=15.9Hz,1H),6.30-6.22(m,1H), 5.35(t,J=9.4 Hz, 1H), 5.23 (t,J=9.6 Hz, I H),5.13 (t,J=9.7 Hz, I H), 4.5 3 (d,J=9.8 Hz, I H),4.40(d,J=9.9 Hz,1H),4.01-3.90(m,2H), 3.73(s,3H), 3.26(dd,J=1.2,7.1 Hz,2H), 2.21(s,3H),2.18(s,3H), 2.11(s,3H), 2.02(s,3H), 1.77(s,3H).

(2S,3S,4R,5S,6R)-2-(3-(4-(4-Methoxy-4-oxobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate

(2S,3S,4R,5S,6R)-2-(3-(4-((E)-4-methoxy-4-oxobut-1-en-1-yl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate (6.8 g), methanol (60 ml), tetrahydrofuran (60 ml), 5%palladium on carbon (1.4 g) were added into a 250 ml reaction flask,hydrogen replacement was carried out for 3 times, and the mixture wasstirred at room temperature for 4 h. The reaction solution was filteredwith diatomite, the filtrate was concentrated under reduced pressure,and purified by column chromatography to obtain 5.6 g of pale yellowsolid.

4-(2-methyl-5-(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyricacid

(2S,3S,4R,5S,6R)-2-(3-(4-(4-Methoxy-4-oxobutyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (5.6 g), methanol (30 ml),tetrahydrofuran (15 ml) and water (30 ml) were added into a 250 mlreaction flask, then lithium hydroxide monohydrate (4.0 g) was slowlyadded, and after addition, the mixture was stirred at room temperaturefor 4 h. The reaction solution was diluted with water, extracted withethyl acetate for three times, the organic phase was discarded, the pHof the aqueous phase was adjusted to 1 with diluted hydrochloric acid,extracted with ethyl acetate for three times, the organic phases werecombined, washed once with saturated salt solution, and dried onanhydrous sodium sulfate, filtered, the filtrate was concentrated underreduced pressure to obtain 2.8 g of white solid. ¹H NMR(400MHz,DMSO-d6):δ12.04(s,IH), 7.11-7.04(m,7H),5.22(d,J=5.5Hz,1H),5.13(brs,1H), 4.88(d,J=5.4 Hz,1H), 4.33(d,J=9.4 Hz,1H), 4.05(d,J8.9 Hz,1H), 3.91(s,2H), 3.29-3.15(m,3H), 2.53(t,J=7.4 Hz,2H),2.20(t,J=7.4 Hz,2H), 2.17(s,3H), 2.03(s,3H), 1.80-1.72 (quin,J=7.7Hz,2H). MS:m/z 445.2,[M-H]⁻.

Intermediate:3-((4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)oxy)propionic acid

Chloro-4-methylphenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone

(3aS,5R,6S,6aS)-6-Hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholinyl)methanone(5.0 g), tetrahydrofuran (50 ml) were added into a 250 ml reactionflask, under nitrogen protection, cooled to 0° C., tert-butylmagnesiumchloride (1 M in THF, 20.1 mL) was added and stirred for 30 min.

2-Chloro-4-iodotoluene (5.5 g), tetrahydrofuran (50 ml) were added intoa 500 ml reaction flask, under nitrogen protection, cooled to -78° C.,n-butyllithium (1.6 M in hexane, 14.9 ml) was slowly add, and stirredfor 10 minutes after addition. The newly prepared Grignard reactionsolution above was added, and after addition, the mixture was returnedto room temperature and stirred for 1 h. The reaction solution waspoured into saturated aqueous ammonium chloride solution, extracted withethyl acetate for three times, the organic phases were combined, washedwith saturated salt solution, dried on anhydrous sodium sulfate,filtered, concentrated under reduced pressure, and purified by columnchromatography to obtain 4.0 g of white solid.

(3aS,5S,6R,6aS)-5-((S)-(3-chloro-4-methylphenyl)(hydroxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol

Chloro-4-methylphenyl)(3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone(3.0 g), cerium chloride heptahydrate (4.3 g) and methanol (60 ml) wereadded into a 250 ml reaction flask, cooled to 0° C. in an ice bath, andsodium borohydride (0.4 g) in 1 M aqueous sodium hydroxide solution (5ml) was slowly added dropwise. After addition, the mixture was returnedto room temperature and stirred for 1 h. The reaction solution waspoured into saturated aqueous ammonium chloride solution, extracted withethyl acetate for three times, the organic phases were combined, washedwith saturated salt solution once, dried on anhydrous sodium sulfate,filtered, concentrated, to obtain 3.0 g of pale yellow solid.

(2R,3S,4R,5S,6S)-6-(3-Chloro-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate

(3aS,5S,6R,6aS)-5-((S)-(3-chloro-4-methylphenyl)(hydroxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (3.0 g), glacial acetic acid (15 ml) and water(15 ml) were added into a 150 ml reaction flask, heated to 110° C. andstirred for 4 h. The reaction solution was concentrated to dryness,azeotropically distilled with toluene for three times, the residue wasdissolved in 30 ml of acetonitrile, triethylamine (13.3 ml) was added,and a solution(18 ml) of acetic anhydride (9.0 ml) in acetonitrile wasslowly added dropwise at 35° C. After addition, the mixture was cooledto room temperature and stirred for 15 h. The reaction solution wasdiluted with ethyl acetate, water was added, and liquid separation wascarried out. The aqueous phase was extracted with ethyl acetate forthree times. The organic phases were combined, washed once with dilutedhydrochloric acid, and once with saturated salt solution, dried onanhydrous sodium sulfate, filtered and concentrated to obtain 4.6 g ofbrown oily substance, which is directly added to the next reaction.

(2S,3S,4R,5S,6R)-2-(3-Chloro-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate

(2R,3S,4R,5S,6S)-6-(3-Chloro-4-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayltetraacetate (4.6 g (theoretical amount)), thiourea (1.5 g), 1,4-dioxane(40 ml), trimethylsilyl trifluoromethanesulfonate (3.5 ml) were addedinto a 150 ml reaction flask, heated to 90° C. and stirred for 2 h. Thereaction solution was cooled to room temperature, iodomethane (1.8 ml)and N,N-diisopropylethylamine (9.5 ml) were added, and the mixture wasstirred for 15 h. Ethyl acetate and water were added to the reactionsolution, and liquid separation was conducted. The aqueous phase wasextracted with ethyl acetate for three times, the organic phases werecombined, washed once with diluted hydrochloric acid, once withsaturated salt solution, dried on anhydrous sodium sulfate, filtered,and concentrated under reduced pressure, and purified by columnchromatography to obtain 2.4 g of pale yellow solid. ¹H NMR(CDCl₃,400MHz):δ7.33(d,J=1.6 Hz,1H), 7.21(d,J 7.9 Hz,1H),7.17-7.14(dd,J 1.6,7.8Hz,1H),5.36(t,J 9.4 Hz,1H),5.23(t,J 9.7 Hz,1H), 5.10(t,J=9.7Hz,1H),4.55(d,J=9.9 Hz, 1H),4.41(d,J=9.9 Hz,1H),2.37(s,3H),2.22(s,3H),2.12(s,3H),2. 04(s,3H),1.87(s,3H).MS:m/z453.1,[M+Na]⁺.

(2S,3S,4R,5S,6R)-2-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate

(2S,3S,4R,5S,6R)-2-(3-Chloro-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate (1.2 g), bis(pinacolato)diboron (1.4 g), potassium acetate(0.8 g), palladium acetate (0.05 g),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.1 g), 1,4-dioxane (10ml) were added into a 25 ml microwave tube, after nitrogen replacement,the mixture was heated to 60° C. by microwave and stirred for 18 h. Thereaction solution was concentrated, and then purified by columnchromatography to obtain 1.1 g of pale yellow solid. ¹H NMR(CDCl₃,400MHz): δ7.67(d,J=2.0 Hz,1H), 7.37(dd,J=2.1,8.0 Hz,1H), 7.17(d,J=7.9 Hz,1H), 5.36(t,J=9.4 Hz,1H), 5.24(t,J=9.6 Hz,1H), 5.15(t,J=9.7 Hz,1H),4.54(d,J 9.9 Hz,1H), 4.46(d,J 9.9 Hz,1H), 2.52(s,3H), 2.20(s,3H),2.12(s,3H), 2.03(s,3H), 1.85(s,3H), 1.35(d,J=3.3 Hz, 12H). MS:m/z545.2,[M+Na]⁺.

Ethyl 3-(4-formylbenzyl)oxy)propionate

p-Hydroxymethylbenzaldehyde (3.0 g) and tetrahydrofuran (30 ml) wereadded into a 150 ml reaction flask, cooled to 0° C. in an ice bath, anda solution of ethyl 3-bromopropionate (14.1 ml) in tetrahydrofuran (15ml) was slowly added ropwise, and the mixture was returned to roomtemperature and stirred for 15 h after addition. The reaction solutionwas poured into saturated aqueous ammonium chloride solution, extractedwith ethyl acetate for three times, the organic phases were combined,washed once with saturated salt solution, dried on anhydrous sodiumsulfate, filtered, concentrated under reduced pressure, and purified bycolumn chromatography to obtain 800 mg of colorless liquid. ¹HNMR(CDCl₃,400 MHz):δ 10.03(s,1H),7.89(d,J=8.2 Hz,2H), 7.52( d,J=8.0Hz,2H),4.64(s,2H),4.19( q,J=7.1 Hz,2H),3.82(t,J=6.3 Hz,2H),2.66(t,J=6.3Hz,2H), 1.29 (t,J=7.1 Hz,3H).

Ethyl 3-(4-(hydroxymethyl)benzyloxy)propionate

Ethyl 3-(4-Formylbenzyl)oxy)propionate (800 mg) and methanol (16 ml)were added into a 50 ml reaction flask, cooled to 0° C. in an ice bath,sodium borohydride (193 mg) was added in batches. After addition, themixture was returned to room temperature and stirred for 2 h. Thereaction solution was poured into 1N HCl aqueous solution, extractedwith ethyl acetate for three times, the organic phases were combined,washed once with saturated salt solution, dried on anhydrous sodiumsulfate, filtered, concentrated under reduced pressure, and purified bycolumn chromatography to obtain 600 mg of colorless liquid. ¹HNMR(CDCl₃,400 MHz):δ7.36-7.32(m,4H),4.68(s,2H),4.54(s,2H),4.17(q,J=7.2Hz,2H),3.75(t,J=6.4 Hz,2H),2.62(t,J=6.4 Hz,2H),2. 07(brs,1H),1.27(t,J=7.1 Hz,3H).

Ethyl 3-((4-(((methoxycarbonyl)oxy)methyl)benzyl)oxy)propionate

Ethyl 3-(4-(hydroxymethyl)benzyloxy)propionate (600 mg), pyridine (0.4ml), dichloromethane (6 ml) were added into a 50 ml reaction flask,cooled to 0° C. in an ice bath, a solution (2 ml) of methylchloroformate (0.5 ml) in dichloromethane was added dropwise, and afteraddition, the mixture was returned to room temperature and stirred for 3h. The reaction solution was poured into 1N HCl aqueous solution,extracted with ethyl acetate for three times, the organic phases werecombined, washed once with saturated salt solution, dried on anhydroussodium sulfate, filtered and concentrated, and purified by columnchromatography to obtain 620 mg of colorless liquid. ¹H NMR(CDCl₃,400MHz):δ7.41-7.34(m,4H),5.17(s,2H),4.55(s,2H),4.18(q,J=7.1 Hz,2H),3.81(s,3H),3.76(t,J=6.4 Hz,2H),2.63 (t,J=6.4 Hz,2H), 1.28(t,J=7.1Hz,3H).

(2S,3S,4R,5S,6R)-2-(3-(4-(3-ethoxy-3-oxopropyloxy)methyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate

1,4-Bis(diphenylphosphino)butane (72 mg), allylpalladium(II) chloridedimer (32 mg), toluene (4 ml), isopropanol (2 ml) were added into a 25ml there-necked flask, after nitrogen replacement, the mixture wasstirred at room temperature for 30 min.

(2S,3S,4R,5S,6R)-2-(4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate (911 mg), Ethyl3-((4-(((methoxycarbonyl)oxy)methyl)benzyl)oxy)propionate andisopropanol (8 ml) were added into a 25 ml microwave reaction tube, theabove catalyst was added after nitrogen replacement, and the reactionwas microwaved to 80° C. for 12 h. The reaction solution wasconcentrated under reduced pressure and purified by columnchromatography to obtain 540 mg of an oily substance. ¹H NMR(CDCl₃,400MHz):67.23(d,J=8.1 Hz,2H),7.18-7.13(m,2H),7.07-7.05(m,3H),5.34 (t,J=9.4Hz,1H),5.22(t,J=9.6 Hz,1H),5.13(t,J=9.7 Hz,1H),4.53(d,J=9.9Hz,1H),4.50(s,2H),4.40(d,J= 9.8 Hz,1H),4.15(q,J=7.2Hz,2H),4.00-3.92(m,2H),3.75(t,J=6.4 Hz,2H),2.61(t,J=6.4 Hz,2H),2.21(s,3H),2.18(s,3H),2.11(s,3H),2.02(s,3H), 1.76(s,3H), 1.27(t,J=6.4Hz,3H).

3-((2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)oxy)propionicacid

(2S,3S,4R,5S,6R)-2-(3-(4-(3-ethoxy-3-oxopropyloxy)methyl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyltriacetate (540 mg), methanol (3 ml), tetrahydrofuran (1.5 ml), water (3ml), lithium hydroxide monohydrate (368 mg) were added into a 25 mlreaction flask, stirred at room temperature for 15 h. The reactionsolution was diluted with water, extracted with ethyl acetate for threetimes, the organic phase was discarded, the pH of the aqueous phase wasadjusted to 1 with diluted hydrochloric acid, extracted with ethylacetate for three times, the organic phases were combined, washed oncewith saturated salt solution, dried on anhydrous sodium sulfate, andfiltered, the filtrate was concentrated to dryness to obtain 300 mg of acolorless foam.

¹HNMR(DMSO-d6,400 MHz):δ12.19(brs,1H),7.22(d,J=8.1Hz,2H),7.13-7.11(m,5H),5.22 (brs, 1H),4.89(brs,1H),4.42(s,2H),4.33(d,J=9.4 Hz,1H),4.05(d,J=9.1Hz,1H),3.94(s,2H),3.61(t,J=6.3 Hz,2H),3.51-3.45(m,1H),3.30-3.17(m,3H),2.48(t,J 6.3Hz,2H),2.18(s,3H),2.04(s,3H). ¹³CNMR(DMSO-d6,100MHz):δ173.2,140.0,138.7,137.9,136.3,135.8,130.1,129.7,128.9,128.1,126.0,85.8,81.8,78.6,74.8,72.7,72.2,66.0,38.9,35.2,19.5,11.5.MS:m/z 485.2,[M+Na]⁺.

Intermediate: N¹-methyl-N¹-(prop-2-yn-1-yl)eth-1,2-diamine

2-(Boc-amino)ethyl Bromide

Tetrahydrofuran (4 ml), water (4 ml), bromoethylamine hydrobromic acid(2.05 g), were successively added into a 25 ml reaction flask, cooled to10° C., and sodium bicarbonate (2.1 g), 4-dimethylaminopyridine (61 mg),di-tert-butyl dicarbonate (2.05 g) were added, and stirred at 10° C. for8 h after addition. The reaction solution was filtered, the filtrate wassubjected to liquid seperation, the aqueous phase was extracted twicewith dichloromethane, the organic phases were combined, washed once withsaturated salt solution, dried with anhydrous sodium sulfate, andconcentrated under reduced pressure to obtain 2.0 g of a pale yellowliquid.

N¹-methyl-N¹-(prop-2-yn-1-yl)eth-1,2-diamine

N-methylpropargylamine (0.68 g), tetrahydrofuran (20 ml), water (20 ml),potassium carbonate (2.46 g, 17.8 mmol) and a solution (5 ml) of2-(Boc-amino)ethyl bromide (2.0 g) in tetrahydrofuran were successivelyadded into a 100 ml reaction flask, and stirred at room temperature for2 h after addition. The reaction solution was extracted with ethylacetate for three times, washed with saturated salt solution, dried onanhydrous sodium sulfate, filtered and concentrated to obtain 1.72 g ofa pale yellow oily substance. The obtained crude product was dissolvedin acetonitrile (10 ml), concentrated hydrochloric acid (5 ml) wasslowly added dropwise, stirred at room temperature for 1 h, the reactionsolution was concentrated under reduced pressure, dissolved in 10 ml ofacetonitrile, potassium carbonate (3.35 g, 24.3 mmol) was added, andstirred at 35° C. for 3 h, cooled to room temperature, filtered withdiatomite, washed with acetonitrile, and the filtrate was concentratedto dryness to obtain 0.67 g of a pale yellow liquid. MS: m/z 112.9,[M+H]⁺.

Intermediate:2-amino-2-methyl-N-(2-(methyl(prop-2-yn-1-yl)amino)ethyl)propionamide

2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (894 mg) anddichloromethane (25 ml) were added into a 50 ml reaction flasksuccessively, cooled to 0° C. in an ice bath, CDI (713 mg) was slowlyadded. After addition, the mixture was stirred at 0° C. for 30 minutes.N¹-Methyl-N¹-(prop-2-yn-1-yl)eth-1,2-diamine (450 mg) was added, andafter addition, the mixture was returned to room temperature and stirredfor 3 h. The reaction solution was diluted with dichloromethane, waterwas added, and the liquid separation was carried out, the aqueous phasewas extracted with dichloromethane for three times, the organic phaseswere combined, washed once with saturated salt solution, dried onanhydrous sodium sulfate, and concentrated to dryness under reducedpressure to obtain 1.04 g of a pale yellow liquid. The product wasdissolved in acetonitrile (5 ml), concentrated hydrochloric acid (2 ml)was slowly added dropwise, stirred at room temperature for 1 h, thereaction solution was concentrated to dryness, acetonitrile (10 ml) wasadded to dissolve, potassium carbonate (1.93 g) was added, stirred at35° C. for 3 h, and cooled to room temperature, filtered with diatomite,washed with acetonitrile, and the filtrate was concentrated underreduced pressure to obtain 550 mg of a pale yellow liquid. MS:m/z198.2,[M+H]⁺.

Intermediate: 2-amino-N-(2-(dimethylamino)ethyl)-2-methylpropionamide

2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (2.03 g) anddichloromethane (25 ml) were added into a 50 ml reaction flasksuccessively, cooled to 0° C. in an ice bath, CDI (1.62 g) was slowlyadded. After addition, the mixture was stirred at 0° C. for 30 minutes.N,N-Dimethylethylenediamine (970 mg) was added, and after addition, themixture was returned to room temperature and stirred for 3 h. Thereaction solution was diluted with dichloromethane, water was added, andthe liquid separation was carried out, the aqueous phase was extractedwith dichloromethane for three times, the organic phases were combined,washed once with saturated salt solution, dried on anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain 1.96 g of apale yellow liquid. The product was dissolved in acetonitrile (10 ml),concentrated hydrochloric acid (4 ml) was slowly added dropwise, stirredat room temperature for 1 h, the reaction solution was concentrated todryness, acetonitrile (10 ml) was added to dissolve, potassium carbonate(4.14 g, 30 mmol) was added, stirred at 35° C. for 3 h, and cooled toroom temperature, filtered with diatomite, washed with acetonitrile, andthe filtrate was concentrated under reduced pressure to obtain 930 mg ofa pale yellow liquid. MS:m/z 174.2,[M+H]+.

Intermediate:2-amino-2-methyl-N-(2-(methyl(2-(methyl(prop-2-yn-1-yl)amino)-2-oxoethyl)amino)ethyl)propionamide

Ethyl N-(2-((tert-butoxycarbonyl)amino)ethyl)-N-methylglycine

Tert-butyl 2-(methylamino)ethylcarbamate (8.7 g), acetonitrile (100 ml),potassium carbonate (10.4 g) and ethyl bromoacetate (9.2 g) weresuccessively added into a 100 ml reaction flask, heated to 35° C. andstirred for 10 h. The reaction solution was filtered, the filtrate wasconcentrated under reduced pressure, and purified by columnchromatography to obtain 9.89 g of pale yellow oily substance.

2-(Aminoethyl)(methyl)amino)-N-methyl-N-(prop-2-yn-1-yl)acetamide

Ethyl N-(2-((tert-butoxycarbonyl)amino)ethyl)-N-methylglycine (5.5 g),tetrahydrofuran (25 ml), lithium hydroxide monohydrate (0.98 g) andwater (2 ml) were successively added into a 50 ml reaction flask, andstirred at room temperature for 5 h. The reaction solution wasconcentrated under reduced pressure, the concentrated residue wasdissolved in dichloromethane (25 ml). HATU (9.62 g), DIPEA (5.57 g) andN-methylpropargylamine (1.75 g) were added successively, and the mixturewas stirred at room temperature for 3 h. The reaction solution wasdiluted with dichloromethane, water was added, and the liquid separationwas carried out. The organic phase was washed once with saturated saltsolution, dried on anhydrous sodium sulfate, concentrated under reducedpressure, and purified by column chromatography to obtain 3.2 g of paleyellow oily substance. The product was dissolved in acetonitrile (15ml), and concentrated hydrochloric acid (5 ml) was slowly addeddropwise, and the mixture was stirred at room temperature for 1 h. Thereaction solution was concentrated, acetonitrile (15 ml) was added todissolve, potassium carbonate (6.24 g) was added, and the mixture wasstirred at 35° C. for 3 h. The reaction solution was cooled to roomtemperature, filtered with diatomite, washed with acetonitrile, and thefiltrate was concentrated to obtain 1.67 g of pale yellow liquid.

2-Aminomethyl-N-(2-(methyl(2-(methyl(propyn-1-yl)amino)oxoethyl)amino)ethyl)propionamide

2-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (2.03 g) anddichloromethane (25 ml) were added into a 50 ml reaction flasksuccessively, cooled to 0° C. in an ice bath, CDI (1.62 g) was slowlyadded. After addition, the mixture was stirred at 0° C. for 30 minutes.2-((2-Aminoethyl)(methyl)amino)-N-methyl-N-(prop-2-yn-1-yl)acetamide(1.67 g) was added, and returned to room temperature and stirred for 3 hafter addition. Dichloromethane was added into the reaction flask todilute, water was added, and the liquid separation was carried out. Theaqueous phase was extracted with dichloromethane for three times, theorganic phases were combined, washed once with saturated salt solution,dried on anhydrous sodium sulfate, concentrated to dryness under reducedpressure, and purified by column chromatography to obtain 2.1 g of paleyellow oily substance. The product was dissolved in acetonitrile (10ml), and concentrated hydrochloric acid (4 ml) was slowly addeddropwise, and the mixture was stirred at room temperature for 1 h. Thereaction solution was concentrated to dryness, acetonitrile (10 ml) wasadded to dissolve, potassium carbonate (3.15 g, 22.8 mmol) was added,and the mixture was stirred at 35° C. for 3 h. The reaction solution wascooled to room temperature, filtered with diatomite, washed withacetonitrile, and the filtrate was concentrated to dryness under reducedpressure to obtain 1.24 g of pale yellow oily substance. MS:m/z269.2,[M+H]⁺.

Preparation of the Compounds Example 1

\4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyricacid (100 mg), N-(2-aminoethyl)pyrrolidine (51 mg), tetrahydrofuran(3ml), N,N-diisopropyl ethylamine (85 mg, 0.66 mmol) and2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethylurea hexafluorophosphate(110 mg) were added into a 50 ml single-neck flask, and stirred at roomtemperature for 2 hours. After the reaction was completed, saturatedaqueous ammonium chloride solution was added to dilute, extracted withethyl acetate, the organic phases were combined, washed once withsaturated salt solution, dried on anhydrous sodium sulfate, filtered,concentrated, and purified by silica gel column chromatography to obtain20 mg of a white solid. ¹H NMR(400MHz,CD30D₃):δ=7.24-7.01(m,7H),4.41(d,J=9.4 Hz,1H), 4.15(d,J=9.2 Hz, 1H),3.97(s,2H),3.51-3.40(m,8H),3.29(t,J=6.0 Hz,2H),2.62(t,J=7.5Hz,2H),2.31-2.24(m,2H),2.23(s,3H),2.16(s,3H),2.12-2.05(m,3H),2.04(s,2H), 1.96-1.91(m,2H).MS:m/z543.3,[M+H]⁺.

Example 2

4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyricacid (100 mg), 4-methyl-1-piperazineethylamine (64 mg), tetrahydrofuran(3ml), N,N-diisopropyl ethylamine (85 mg) and 2-(7-benzotriazoleoxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg) wereadded into a 50 ml single-neck flask, and stirred at room temperaturefor 2 hours after addition. After the reaction was completed, saturatedaqueous ammonium chloride solution was added to dilute, extracted withethyl acetate, the organic phases were combined, washed once withsaturated salt solution, dried on anhydrous sodium sulfate, filtered,concentrated, and purified by silica gel column chromatography to obtain56 mg of a white solid. ¹H NMR(400MHz,CD30D₃):δ=7.23-7.04(m,7H),4.42(d,J= 9.5 Hz,1H), 4.16(d,J=9.3 Hz,1H),3.97(s,2H),3.53-3.37(m,4H),3.37-3.29(m,5H),3.27-2.92(m,4H),2.80(s,3H),2.66-2.54(m,4H),2.27-2.18(m,5H),2.16(s,3H),1.97-1.85(m,2H).MS:m/z 572.3,[M+H]⁺.

Example 3

4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyricacid (80 mg), 1-(2-aminoethyl)piperazine (30 mg), tetrahydrofuran (3ml), N,N-diisopropyl ethylamine (70 mg) and 2-(7-benzotriazoleoxide)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (89 mg) wereadded into a 50 ml single-neck flask, and stirred at room temperaturefor 2 hours after addition. After the reaction was completed, saturatedaqueous ammonium chloride solution was added to dilute, extracted withethyl acetate, the organic phases were combined, washed once withsaturated salt solution, dried on anhydrous sodium sulfate, filtered,concentrated, and purified by silica gel column chromatography to obtain16 mg of a white solid. ¹H NMR (400MHz,CD30D₅):57.22-7.05(m,7H),4.41(d,J=9.4 Hz, 1H), 4.15(d,J 9.2 Hz,1H),3.97(s,2H), 3.53-3.38(m,5H),3.17(t,J=6.0 Hz,2H),2.62(t,J=7.4Hz,2H),2.30-2.20(m,5H),2.16(s,3H),1.97-1.78(m,4H),1.74-1.57(m,2H),1.36-1.28(m,6H).MS:m/z 557.3,[M+H]⁺.

Example 4

4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyricacid (80 mg), N¹-benzyl-N¹-methylethane-1,2-diamine (30 mg),tetrahydrofuran (3 ml), N,N-diisopropyl ethylamine (70 mg) and2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (89 mg) were added into a 50 ml single-neck flask,and stirred at room temperature for 2 hours after addition. After thereaction was completed, saturated aqueous ammonium chloride solution wasadded to dilute, extracted with ethyl acetate, the organic phases werecombined, washed once with saturated salt solution, dried on anhydroussodium sulfate, filtered, concentrated, and purified by silica gelcolumn chromatography to obtain 50 mg of a white solid. ¹H NMR(400MHz,CD₃OD):δ=7.39-7.25(m,5H),7.22-7.12(m,3H),7.11-7.03(m,4H),4.40(d,J=9.4Hz,1H),4.14(d,J=9.1Hz,1H),3.96(s,2H),3.67(s,2H),3.52-3.34(m,5H),2.67-2.53(m,4H),2.33(s,3H),2.24-2.16(m,5H),2.15(s,3H),1.94-1.83(m,2H).MS:m/z593.3,[M+H]⁺.

Example 5

4-(2-Methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butyric acid (prepared by the method of ReferenceJournal of Medicinal Chemistry 2017,60,710-721) (89 mg, 0.2 mmol),N,N-dimethylformamide (5 ml), N,N-diisopropylethylamine (52 mg, 0.4mmol), N¹-methyl-N¹-(prop-2-yn-1-yl)ethane-1,2-diamine (Compound 1B) (25mg, 0.22 mmol), 2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (84 mg, 0.22 mmol) were added successively into a 25ml reaction flask, and stirred at room temperature for 2 hours. Thereaction solution was diluted with dichloromethane, washed with water,the aqueous phase was extracted with dichloromethane for three times,the organic phases were combined, washed with saturated salt solution,dried on anhydrous sodium sulfate, filtered, the filtrate wasconcentrated to dryness, and purified by column chromatography(dichloromethane: methanol = 20:1) to obtain a white solid (45 mg). ¹HNMR(400 MHz,DMSO-d6):δppm7.17-7.12(m,2H),7.09-7.02(m,5H),6.22-6.20(t,J=4.9 Hz,1H),4.36-4.34(d;J=9.5 Hz,1H), 4.13-4.11(d,J=9.4 Hz,IH),3.96-3.88(m,2H),3.63-3.58(t,J=8.8 Hz,IH),3.51-3.44(m,2H),3.28-3.25(m,4H),2.62-2.58(t,J=7.2Hz,2H),2.54-2.51(t,J=5.8 Hz,2H),2.26-2.22(m,7H),2.15(s,3H),2.14-(t,J=7.8 Hz,2H), 1.97-1.88(m,2H).¹³C NMR(100MHz,DMSO-d6):δppm 168.5,134.8,134.4,133.0,132.2,130.7,125.7,124.2,124.1,123.9,120.8,80.9,77.2,73.2,72.9,69.9,69.0,67.3,49.4,40.9,36.5, 34.1,31.8,30.9,30.0,22.3,14.8,7.0; MS[M+H]⁺=541.3.

Example 6

The compound was obtained by referring to the similar preparation schemein Example 1, ESI-MS: 543.3 [M+H]⁺.

The specific preparation method was as follows:

3-(2-Methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyloxy)propionicacid (91 mg), N,N-dimethylformamide (10 ml), N,N-diisopropylethylamine(55 mg), N¹-methyl-N¹-(prop-2-yn-1-yl)ethane-1,2-diamine (27 mg),2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(92 mg) was added successively into a 50 ml reaction flask, and stirredat room temperature for 2 hours after addition. The reaction solutionwas diluted with dichloromethane, washed with water, the aqueous phasewas extracted with dichloromethane for three times, the organic phaseswere combined, washed with saturated salt solution, dried on anhydroussodium sulfate, filtered, the filtrate was concentrated to dryness, andpurified by column chromatography to obtain a white solid (53 mg).

Example 7

The compound was obtained by referring to the similar preparation schemein Example 1.

The specific preparation method was as follows:

3-(2-Methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)benzyl)oxy)propionicacid (92 mg), N,N-dimethylformyl (5 ml), N,N-diisopropylethylamine (52mg), N¹-methyl-N¹-(prop-2-yn-1-yl)eth-1,2-diamine (25 mg),2-(7-benzotriazole oxide)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (84 mg) was added successively into a 25 ml reactionflask, and stirred at room temperature for 2 hours. The reactionsolution was diluted with dichloromethane, washed with water, theaqueous phase was extracted with dichloromethane for three times, theorganic phases were combined, washed with saturated salt solution, driedon anhydrous sodium sulfate, filtered, the filtrate was concentrated todryness, and purified by column chromatography to obtain 45 mg of awhite solid. ¹H NMR(400MHz,DMSO-d6):δ7.82(s,1H),7.22-7.10(m,7H),5.22(s,1H),5.13(s,1H),4.88(s,1H),4.40(s,2H),4.33(d,J=9.0 Hz,1H),4.05(d,J=8.3Hz,1H),3.94(s,2H),3.60(s,2H),3.51(s,1H),3.29-3.21(m,5H),2.39-2.34(m,4H),2.18(m,5H),2.04(s,3H).¹³CNMR(100 MHz,DMSO-d6):δ170.5, 139.9, 138.7,137.9,136.4,135.8,130.1,129.7,128.9,128.1,126.0,85.8,81.8,79.3,78.6,76.3,74.8,72.7,72.1,66.6,54.7,45.5,41.7,38.9,37.1,36.6,19.5,11.5.MS:m/z557.2737,[M+H]⁺.

Example 8

The compound was obtained by referring to the similar preparation schemein Example 1, ESI-MS: 539.2[M+H]⁺.

The specific preparation method was as follows:

(E)(4-(2-Methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)vinylaceticacid (102 mg), N,N-dimethylformamide (10 ml), N,N-diisopropylethylamine(54 mg), N¹-methyl-N¹-(prop-2-yn-1-yl)ethane-1,2-diamine (29 mg),2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(95 mg) was added successively into a 50 ml reaction flask, and stirredat room temperature for 2 hours after addition. The reaction solutionwas diluted with dichloromethane, washed with water, the aqueous phasewas extracted with dichloromethane for three times, the organic phaseswere combined, washed with saturated salt solution, dried on anhydroussodium sulfate, filtered, the filtrate was concentrated to dryness, andpurified by column chromatography to obtain a white solid (56 mg).

Example 9

The compound was obtained by referring to the similar preparation schemein Example 1, ESI-MS: 553.4[M+H]⁺.

The specific preparation method was as follows:

3-(2-Ethynyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyloxy)propionicacid (65 mg), N,N-dimethylformamide (8 ml), N,N-diisopropylethylamine(50 mg), N¹-methyl-N¹-(prop-2-yn-1-yl)ethane-1,2-diamine (20 mg),2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(82 mg) was added successively into a 50 ml reaction flask, and stirredat room temperature for 1.5 hours after addition. The reaction solutionwas diluted with dichloromethane, washed with water, the aqueous phasewas extracted with dichloromethane for three times, the organic phaseswere combined, washed with saturated salt solution, dried on anhydroussodium sulfate, filtered, the filtrate was concentrated to dryness, andpurified by column chromatography to obtain a white solid (16 mg).

Example 10

The compound was obtained by referring to the similar preparation schemein Example 1, ESI-MS: 555.6[M+H]⁺.

The specific preparation method was as follows:

5-(2-Methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)pheny)valericacid (49 mg), N,N-dimethylformamide (5 ml), N,N-diisopropylethylamine(25 mg), N¹-methyl-N¹-(prop-2-yn-1-yl)ethane-1,2-diamine (18 mg),2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(62 mg) was added successively into a 25 ml reaction flask, and stirredat room temperature for 2 hours after addition. The reaction solutionwas diluted with dichloromethane, washed with water, the aqueous phasewas extracted with dichloromethane for three times, the organic phaseswere combined, washed with saturated salt solution, dried on anhydroussodium sulfate, filtered, the filtrate was concentrated to dryness, andpurified by column chromatography to obtain a pale yellow solid (19 mg).

The introduction of the “alkynyl” functional group into some compoundsof the present invention has two advantages: on the one hand, the“alkynyl” functional group can use “Click chemistry” to connectbioluminescent markers, which is beneficial to accurately determine thedistribution of the compound in the body. For example, “click chemistry”occurs between the compounds of present invention and “azide” compoundswith fluorescent chromophores, under the catalysis of copper salts, togenerate fluorescent compounds with “triazole structure”. The compoundsof the present invention can also be linked with other biologicalcompounds with biomarker functions to form new chemical substances thatare easy to detect, which is of great significance to fully study theeffectiveness and safety of such compounds. On the other hand, the“alkynyl” functional group connects with other pharmacophore groupsthrough “Click chemistry”, which is conducive to finding candidatecompounds with better comprehensive properties. Examples were asfollows:

Exploratory Research Using “Click Chemistry” Preparation of LabeledCompounds With Luminescent Properties

The compound of Example 5, copper sulfate, and 7-hydroxy-3-azidocoumarin(refer to Journal of the American Chemical Society(2014),136(20),7205-7208; Chemistry-A European Journal(2011), 17(12),3326-3331,S3326/1-S3326/21; Journal of Fluorescence(2013),23(1),181-186;Journal of Organic Chemistry (2011), 76(12), 4964-4972; AngewandteChemie, InternationalEdition(2019), 58(21), 6987-6992) were reacted atroom temperature to obtain a product, Rf: 0.22(dichloromethane:methanol=10:1).

Preparation of Candidate Compounds With Better Comprehensive Properties

The compound of Example 5, copper sulfate, and cyclopropyl azide (referto Chemische Berichte(1985),118(4),1564-1574 ; Science ofSynthesis(2010),41,543-612 ; Nature(London, United Kingdom) (2019),574(7776), 86-89) were reacted at room temperature to obtain a product.Rf: 0.24 (dichloromethane:methanol=10:1). The compound has similarbiological activity to that of Example 5, and has better lipidsolubility and water solubility than the compound of Example 5.

Biological Test 1. SGLT1 Inhibitor Activity Experiment 1

The inhibitory activity of SGLT1 was tested with reference to the methoddescribed in document (Journal of Medicinal Chemistry 2017, 60, 710-721,Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1(SGLT1)Inhibitor Restricted to the Intestinal Lumen,for the Treatment ofDiabetes).

Test Result Compound Number SGLT1 Activity 1 (Example 5) A 2 (Example 6)A 3 (Example 7) A 4 (Example 8) A

wherein A represents: activity IC₅₀<50 nM, B represents 50 nM<IC₅₀<1000nM, C represents IC₅₀>1000 nM,

The experimental results show that the compounds of the presentinvention have significant activity of inhibiting SGLT1.

In the mouse glucose tolerance test, the compounds of the presentinvention have the effect of improving the blood glucose level of thetest animals.

The compounds of the present invention help to reduce body weight, andin in vivo pharmacodynamic studies, the compounds of the presentinvention reduced the body weight of experimental animals.

The compounds of the present invention have very low or no absorption invivo, and pharmacokinetic studies have shown that the compounds of thepresent invention are hardly detected in experimental animals, and havealmost no side effects on other organs in the body.

2. hSGLT1 Inhibitor Activity Experiment

Inhibitory activity testing was performed with reference to a similarmethod described in document (Acta Pharmaceutica Sinica2017,52(6):897-903; Nature Protocols(2007), 2(3), 753-762; Journal ofBiochemical and Biophysical Methods(2005),64(3), 207-215; DiabetesTechnology & Therapeutics(2011), 13(7), 743-775).

In this experiment, the in vitro activity assay was evaluated using theuptake of 2-NBDG(2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose, CAS NO :186689-07-6) by human embryonic kidney epithelial cells (HEK293, stablyexpressing human SGLT1), and the SGLT1 inhibitory activity of the targetcompound was determined by measuring its half-maximal inhibitoryconcentration (IC₅₀).

HEK293 cells that can stably express human SGLT1 gene were inoculatedinto a 96-well clear-bottom black plates containing DMEM medium. Thecells were incubated at 37° C., 5% CO₂ in a cell incubator. The mediumin the 96-well plate was aspirated, and the plate was treated withlow-glucose serum-free DMEM medium, and washed once with non-specificuptake buffer and once with Na⁺-dependent uptake buffer. Uptake buffercontaining test compound was added to each well of cells, followed byuptake buffer containing 2-NBDG for glucose uptake, and the cell platewas incubated at 37° C., 5% CO₂. The compounds were gradiently diluted.The uptake reaction was stopped by removing the culture medium, andafter washing the cells with ice-cold uptake buffer, the washingsolution was removed. The cells were lysed by adding NaOH, and thecontent of 2-NBDG in the cells was detected by a fluorescence microplatereader. The protein concentration of the lysate was measured by BCAmethod, the uptake of 2-NBDG was quantified by fluorescenceintensity/protein content, and the obtained data were analyzed usingGraphPad Prism to determine the median inhibitory concentration (IC₅₀)of the compound to be tested.

The comparative compound 3 is the compound numbered “3” in the document(Journal of Medicinal Chemistry 2017,60,710-721, Discovery of LX2761,aSodium-Dependent Glucose Cotransporter 1 (SGLT 1)Inhibitor Restricted tothe Intestinal Lumen, for the Treatment of Diabetes). It was preparedand identified according to the synthetic method described in thedocument.

Test Result Compound Number SGLT1 Inhibitory Activity(nM) Example 2 0.97Example 3 0.83 Example 4 1.01 Example 5 0.37 Comparative compound 3 57.9

The experimental results show that the compounds of the examples of thepresent invention, for example, Example 2, Example 3, Example 4, Example5, have significant activity of inhibiting SGLT1.

3. Oral Glucose Tolerance Test (OGTT) After Continuous Administration inRats for 14 Days

-   Experimental animals: SPF male SD rats;-   Compound preparation: an appropriate amount of the compounds of    Example 2, Example 3, and Example 5 were weighed, and uniformly    suspended with an appropriate amount of 0.5% CMC-Na solution;-   Preparation of glucose solution: an appropriate amount of glucose    powder was weighed and dissolved with an appropriate amount of pure    water;-   Dosage and method of administration: 0.012 mg/kg, oral gavage.

Experimental process: the animals were fed a normal diet withconsecutive administration for 14 days, and the glucose tolerance testwas performed on day 15, blood glucose was detected beforeadministration (-30 min), before giving glucose (0 min), and 10, 30, 60,and 120 min after giving glucose solution, and the defecation of animalswas observed.

Experimental results: The results in FIG. 1 show that the compounds ofExample 2, Example 3 and Example 5 can significantly reduce the bloodsugar level of rats, and no loose stools were observed in theexperimental animals within 48 hours before and after the experiment.

4. Oral Glucose Tolerance Test (OGTT) After Consecutive Administrationin Mice

-   Experimental animals: SPF male mice;-   Compound preparation: an appropriate amount of the compounds of    Example 5 was weighed, and uniformly suspended with an appropriate    amount of 0.5% CMC-Na solution;-   Preparation of glucose solution: an appropriate amount of glucose    powder was weighed and dissolved with an appropriate amount of pure    water;-   Administration and dosage: oral gavage; blank vehicle group,    high-dose group (1.6 mg/kg), low-dose group (0.12 mg/kg).

Experimental Process

-   (1) The mice were fed a high-sugar diet for 6 days, and then grouped    (10 mice in each group) to enter the administration stage;-   (2) Example compound 5 was administered at 5:00 pm every day from    day 1 to day 5, once a day, and then the animals were fed a    high-sugar free diet, and the defecation of the animals was    observed.-   (3) On day 6, oral glucose tolerance test was performed, and glucose    solution (2 g/kg) was orally administered. Blood glucose was    detected before (0 min) and 10, 30, and 60 min after giving glucose    solution, respectively.

Experimental Results

From day 1 to day 5, the observation of animal defecation aftercontinuous administration is summarized as follows:

Statistics of loose stools in animals Day 1 Day 2 Day 3 Day 4 Day 5high-dose group (1.6 mg/kg) ⅒ 0/10 0/10 0/10 0/10 low-dose group (0.12mg/kg) 0/10 0/10 0/10 0/10 0/10 Note: The data in the table representsthe total number of animals with “loose stool symptoms” and the totalnumber of animals in the group. For example, “⅒” means that one of the10 animals in each group has “loose stool symptoms”.

The results of oral glucose tolerance test (OGTT) on day 6 are shown inFIG. 2 .

Experimental summary: (1) From day 1 to day 5, the compound 5 of Example5 was continuously administered, in the high dose group (1.6 mg/kg),only 1 animal had loose stools on day 1, and the animals did not haveloose stools on day 2 to day 5; in the low-dose group (0.12 mg/kg), theanimals did not have loose stools after continuous administration for 5days.

On day 6, in the oral glucose tolerance test (OGTT), the results in FIG.2 show that both the high and low dose groups of the compound of Example5 can significantly reduce the blood glucose level of mice.

5. Pharmacokinetic Study in Rats

-   Experimental animals: SPF male SD rats;-   Dosage and method of administration: 10 mg/kg, oral gavage.-   Research compound: Dapagliflozin, the compound of Example 5, the    compound of Example 7, the compound of Comparative Example 6;-   Test method: Before administration (0), and 1, 4, 8, and 24 hours    after administration, 0.2 ml of blood was collected from orbital    venous plexus, anticoagulated with heparin, and plasma was    collected.

Note: The comparative compound 6 is the compound numbered “6” in thedocument (Journal of Medicinal Chemistry 2017,60,710-721, Discovery ofLX2761,a Sodium-Dependent Glucose Cotransporter 1 (SGLT 1)InhibitorRestricted to the Intestinal Lumen, for the Treatment of Diabetes). Itwas prepared and identified according to the synthetic method describedin the document.

Pharmacokinetic Absolute Bioavailability Data of Rats: Compound AbsoluteBioavailability(F%) Example 5 0.8% Example 7 1.1% Dapagliflozin 73%Comparative compound 6 23%

The experimental results show that: the compounds of Example 5 andExample 7 had almost no absorption in vivo, and the absolutebioavailability values were all less than 1.5%; while the absolutebioavailability of the comparative compound 6 is 23%, and the absolutebioavailability of dapagliflozin was 73%. Therefore, the comparisoncompound 6 and dapagliflozin were both absorbed into the blood afteroral administration, and their exposure to organs in the body (e.g.,brain, heart and other organs) may lead to potential and unpredictabletoxicity.

In addition to being expressed in the kidney, SGLT1 also exists inintestinal epithelial cells and organs such as the heart and the brain.Compared with the comparative compounds 6 and dapagliflozin, thecompounds of Example 5 and Example 7 of the present invention werehardly detected in vivo after oral administration. Therefore, accordingto preliminary experimental evidence, it is inferred that the compoundsof Example 5 and Example 7 of the present invention have no side effectson various organs such as the heart and brain.

6. In Vivo Hypoglycemic Efficacy Experiment Combined With Sitagliptin

Model establishment: SPF grade Balb/C male mice were used in thisexperiment, and the establishment of the type 2 diabetes mouse model wasinduced by intraperitoneal injection of streptozotocin (STZ)supplemented by high-fat and high-sugar diet.

Group: 10 per group

Administration: normal group, model group, low-dose combinedadministration group (the compound of Example 5 0.02 mg/kg + sitagliptin20 mg/kg), medium-dose combined administration group (the compound ofExample 5 0.06 mg/kg + sitagliptin 20 mg/kg), high-dose combinedadministration group (the compound of Example 5 0.1 mg/kg + sitagliptin20 mg/kg), sitagliptin group (20 mg/kg). The normal group and the modelgroup were given the solvent by gavage.

The experimental results show that the combination of the compound ofExample 5 and sitagliptin can significantly reduce the blood glucoselevel of diabetic model animals, and there is a dose-effectrelationship.

7. Study on Intestinal Microbial Metabolic Stability of the Compounds

Methods: The collected rat feces were processed, and the fecessuspension was obtained for the determination of metabolic stability.The mixed reaction system consisting of the rat feces suspension and thecompound of Example 5 was incubated at 37° C. for 3 h, 6 h, 12 h and 24h. The compound of Example 5 in the incubation system was analyzed todetermine the total amount of remaining compound. Wherein, “+”represents the remaining percentage being: <50%; “++” represents theremaining percentage being: 50% to 70%; “+++” represents the remainingpercentage being: 70% to 90%; “++++” means the remaining percentagebeing: >90%.

Experimental results: Incubation time 3h 6h 12h 24h Remaining percentageof compound of Example 5 ++++ ++++ +++ +++

The test results showed that after the compound of Example 5 wasincubated with microorganisms in rat feces for about 24 hours, theremaining compound of Example 5 was still relatively abundant (>70%). Itwas illustrated that the compound of Example 5 could still maintain highstability under the metabolism of intestinal microorganisms.

8. The compound of the present invention has anti-tumor effect. In theanti-tumor experiment of Hep3B xenograft tumor model, it is found thatthe compound of the present invention can inhibit the growth of tumor;the test on the animal model induced by high-fat diet suggests that thecompounds of the present invention are beneficial to the remission ofnon-alcoholic fatty liver disease and non-alcoholic steatohepatitis, aswell as the treatment of liver and kidney diseases related to energyabsorption and metabolism.

What is claimed is:
 1. A compound of formula (V), a stereoisomer,tautomer or pharmaceutically acceptable salt thereof,

wherein, U, V, W and Q are each independently selected from nitrogenatom or CH; R_(1a), R_(1b), R_(1c) are each independently selected fromhalogen or —OR_(1A), —NHR_(1A), wherein each R_(1A) is independentlyhydrogen, C1-C6 alkyl or acyl; R₂ is selected from —S(O)_(m)—R_(1A);each of R₃, R₄, R₅, R_(6a), R_(7a), R_(6b), R_(7b) is independentlyselected from hydrogen, deuterium, halogen, C1-C6 alkyl or acyl; R_(A),R_(B) are each independently selected from hydrogen, deuterium, alkyl,deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino,mercapto, nitro, hydroxyl, cyano, oxo, C2 ~C8 alkenyl, C2~C8 alkynyl,cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH₂)_(n1)R_(aa),—(CH₂)_(n1)OR_(aa), —SR_(aa), —(CH₂)_(n1)C(O)R_(aa), —SR_(aa),—C(O)OR_(aa), —C(O)R_(aa), —S(O)_(m1)R_(aa), —(CH₂)_(n1)S(O)_(m1)R_(aa),—NR_(aa)R_(bb), —C(O)NR_(aa)R_(bb), —NR_(aa)C(O)R_(bb),—NR_(aa)S(O)_(m1)R_(bb); alternatively R_(A), R_(B) together with thenitrogen atoms to which they are attached form a 3-to 8-memberedheterocycle, the heterocycle may contain one or more carbon, nitrogen,oxygen or sulfur atoms, and may be further substituted by halogen,alkyl, cycloalkyl, aryl, alkoxy, alkenyl, alkynyl, or oxo; R_(aa),R_(bb) are each independently selected from hydrogen, deuterium, alkyl,deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen,cyano, nitro, hydroxy, amino, alkenyl, alkynyl, deuterated alkenyl,deuterated alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl,haloalkoxy, alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl,cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally furthersubstituted by one or more substituents selected from hydrogen,deuterium, silyl, alkylsilyl, substituted or unsubstituted alkyl,halogen, hydroxy, substituted or unsubstituted amino, oxo, nitro, cyano,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted hydroxyalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl and substituted or unsubstituted heteroaryl; Z is selected fromoxygen atom, sulfur atom; n1 =0, 1, 2, 3, 4; m1=0, 1, 2, 3, 4; m = 0, 1,2; q=0, 1, 2,
 3. X is selected from hydrogen, deuterium, halogen, C1-C6alkyl, C3-C6 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl; Y is a linkinggroup selected from the following structures:

wherein, R_(E), R_(F), R_(G), R_(H) are each independently selected fromhydrogen, deuterium, halogen, C1-C6 alkyl or acyl; E, J are selectedfrom chemical bonds, —CH₂—, oxygen, —NH—; s1=0, 1, 2, 3, 4, 5; s2=0, 1,2, 3, 4, 5; s3=0, 1, 2, 3, 4,
 5. 2. The compound of formula (V), thestereoisomer, tautomer or pharmaceutically acceptable salt thereofaccording to claim 1, which is a compound of formula (VA), astereoisomer, tautomer or pharmaceutically acceptable salt thereof,

wherein, R_(1a), R_(1b), R_(1c) are each independently selected fromhalogen or -OR_(1A), -NHR_(1A), wherein each R_(1A) is independentlyhydrogen, C1-C6 alkyl or acyl; R₂ is selected from —S(O)_(m)—R_(1A);each of R₃, R₄, R₅, R_(6b), R_(7b) is independently selected fromhydrogen, deuterium, halogen, C1-C6 alkyl or acyl; R_(A), R_(B) are eachindependently selected from hydrogen, deuterium, alkyl, deuteratedalkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, mercapto, nitro,hydroxyl, cyano, oxo, C2 ~C8 alkenyl, C2~C8 alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, —(CH₂)_(n1)R_(aa), —(CH₂)_(n1)OR_(aa),—SRaa, —(CH₂)_(n1)C(O)R_(aa), —SRaa, —C(O)ORaa, —C(O)Raa,—S(O)_(m1)R_(aa), —(CH₂)_(n1)S(O)_(m1)R_(aa), —NR_(aa)R_(bb),—C(O)NR_(aa)R_(bb), —NR_(aa)C(O)R_(bb), —NR_(aa)S(O)_(m1)R_(bb);alternatively R_(A), R_(B) together with the nitrogen atoms to whichthey are attached form a 3-to 8-membered heterocycle, the heterocyclemay contain one or more carbon, nitrogen, oxygen or sulfur atoms, andmay be further substituted by halogen, alkyl, cycloalkyl, aryl, alkoxy,alkenyl, alkynyl, or oxo; R_(aa), R_(bb) are each independently selectedfrom hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy,hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino,alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl, wherein said alkyl, deuterated alkyl,haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl,deuterated alkenyl, deuterated alkynyl, cycloalkyl, heterocyclyl, aryland heteroaryl, optionally further substituted by one or moresubstituents selected from hydrogen, deuterium, silyl, alkylsilyl,substituted or unsubstituted alkyl, halogen, hydroxy, substituted orunsubstituted amino, oxo, nitro, cyano, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; n1 =0, 1, 2, 3, 4; m1=0, 1, 2, 3, 4; m = 0, 1,2; q=0, 1, 2, 3; X is selected from hydrogen, deuterium, halogen, C1-C6alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; Y is a linkinggroup selected from the following structures:

wherein, R_(E), R_(F), R_(G), R_(H) are each independently selected fromhydrogen, deuterium, halogen, C1-C6 alkyl or acyl; E, J are selectedfrom chemical bonds, —CH₂—, oxygen, —NH—; s1=0, 1, 2, 3, 4, 5; s2=0, 1,2, 3, 4, 5; s3=0, 1, 2, 3, 4,
 5. 3. The compound of formula (V), thestereoisomer, tautomer or pharmaceutically acceptable salt thereofaccording to claim 1, which is a compound of formula (VA-1), astereoisomer, tautomer or pharmaceutically acceptable salt thereof,

wherein, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl,C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; R₅, R_(6b), R_(7b) iseach independently selected from hydrogen, deuterium, halogen, C1-C6alkyl or acyl; R_(A), R_(B) are each independently selected fromhydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy,haloalkoxy, halogen, amino, mercapto, nitro, hydroxyl, cyano, oxo, C2~C8 alkenyl, C2~C8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—(CH₂)_(n1)R_(aa), —(CH₂)_(n1)OR_(aa), —SRaa, —(CH₂)_(n1)C(O)R_(aa),—SRaa, —C(O)ORaa, —C(O)Raa, —S(O)_(m1)R_(aa),—(CH₂)_(n1)S(O)_(m1)R_(aa), —NR_(aa)R_(bb), —C(O)NR_(aa)R_(bb),—NR_(aa)C(O)R_(bb), —NR_(aa)S(O)_(m1)R_(bb); R_(aa), R_(bb) are eachindependently selected from hydrogen, deuterium, alkyl, deuteratedalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano,nitro, hydroxy, amino, alkenyl, alkynyl, deuterated alkenyl, deuteratedalkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein saidalkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy,alkenyl, alkynyl, deuterated alkenyl, deuterated alkynyl, cycloalkyl,heterocyclyl, aryl and heteroaryl, optionally further substituted by oneor more substituents selected from hydrogen, deuterium, silyl,alkylsilyl, substituted or unsubstituted alkyl, halogen, hydroxy,substituted or unsubstituted amino, oxo, nitro, cyano, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted hydroxyalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl and substituted orunsubstituted heteroaryl; n1=0, 1, 2, 3, 4; m1=0, 1, 2, 3, 4; q=0, 1, 2,3; Y is a linking group selected from the following structures:

which is a compound of formula (VA-2), a stereoisomer, tautomer orpharmaceutically acceptable salt thereof,

wherein, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl,C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; each of R₅, R_(6b),R_(7b) is independently selected from hydrogen, deuterium, halogen,C1-C6 alkyl or acyl; q=0, 1, 2, 3; ring B has the following structure:

Y is a linking group selected from the following structures:

.
 4. The compound of formula (V), the stereoisomer, tautomer orpharmaceutically acceptable salt thereof according to claim 1, which isone of the following compounds, stereoisomers, tautomers orpharmaceutically acceptable salts thereof,

which is one of the following compounds, stereoisomers, tautomers orpharmaceutically acceptable salts thereof,

.
 5. A compound of formula (I), a stereoisomer, tautomer orpharmaceutically acceptable salt thereof,

wherein, R₁ is selected from F or —OR_(1A), —NHR_(1A), wherein R_(1A) isindependently hydrogen, C1-C6 alkyl or acyl; R₂ is selected from—S(O)_(m)—R_(1A), m = 0, 1, 2; each of R₃, R₄, R₅, R₆, R₇, R₈, R₉ isindependently selected from hydrogen, deuterium, halogen, C1-C6 alkyl oracyl; m2=0, 1, 2, 3; n2=0, 1, 2, 3; X is selected from hydrogen,deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6alkynyl; Y is a linking group, which is a linking arm composed of 2 to17 carbon, oxygen and nitrogen atoms; Z is O, S or hydrogen.
 6. Acompound of formula (I-1), a stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof,

wherein, R_(1a), R_(1b), R_(1c) are each independently selected from For —OR_(1A), —NHR_(1A), wherein each R_(1A) is independently hydrogen,C1-C6 alkyl or acyl; R₂ is selected from —S(O)_(m)—R_(1A), m = 0, 1, 2;each of R₃, R₄, R₅, R₆, R₇, R₈, R₉ is independently selected fromhydrogen, deuterium, halogen, C1-C6 alkyl, cycloalkyl, cycloalkylalkylor acyl, alkynylalkyl; m2=0, 1, 2, 3; n2=0, 1, 2, 3; X is selected fromhydrogen, deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6alkenyl, C2-C6 alkynyl; Y1 is a linking group selected from thefollowing structures:

wherein, R_(E), R_(F), R_(G), R_(H) are each independently selected fromhydrogen, deuterium, halogen, C1-C6 alkyl or acyl; E, J are selectedfrom chemical bonds, —CH₂—, oxygen, —NH—; s1=0, 1, 2, 3, 4, 5; s2=0, 1,2, 3, 4, 5; s3=0, 1, 2, 3, 4,
 5. 7. The compound of formula (I), thestereoisomer, tautomer or pharmaceutically acceptable salt thereofaccording to claim 5, which includes the compound of the followingstructure of general formula (II), a stereoisomer, tautomer orpharmaceutically acceptable salt thereof,

wherein, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl,C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; R₈, R₉ are selected fromhydrogen, deuterium, halogen, C1-C6 alkyl or acyl; m2=0, 1, 2, 3; n2 =1; Y is a linking group, which is a linking arm composed of 2 to 17carbon, oxygen and nitrogen atoms.
 8. The compound of formula (I-1), thestereoisomer, tautomer or pharmaceutically acceptable salt thereofaccording to claim 6, which includes the compound of the followingstructure of general formula (II-1), a stereoisomer, tautomer orpharmaceutically acceptable salt thereof,

wherein, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl,C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; R₈, R₉ are eachindependently selected from hydrogen, deuterium, halogen, C1-C6 alkyl,cycloalkyl, cycloalkylalkyl or acyl, alkynylalkyl; m2=0, 1, 2, 3; n2 =1; Y1 is a linking group selected from the following structures:

wherein, R_(E), R_(F), R_(G), R_(H) are each independently selected fromhydrogen, deuterium, halogen, C1-C6 alkyl or acyl; E, J are selectedfrom chemical bonds, —CH₂—, oxygen, —NH—; s1=0, 1, 2, 3, 4, 5; s2=0, 1,2, 3, 4, 5; s3=0, 1, 2, 3, 4,
 5. 9. The compound of formula (I-1), thestereoisomer, tautomer or pharmaceutically acceptable salt thereofaccording to claim 8, which includes the compound of the followingstructure of general formula (III), a stereoisomer, tautomer orpharmaceutically acceptable salt thereof,

wherein, X is selected from hydrogen, deuterium, halogen, C1-C6 alkyl,C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl; R₈, R₉ are eachindependently selected from hydrogen, deuterium, halogen, C1-C6 alkyl oracyl; m2=0, 1, 2, 3; n2 = 1; Y1 is a linking group selected from thefollowing structures:

.
 10. The compound of formula (I-1), the stereoisomer, tautomer orpharmaceutically acceptable salt thereof according to claim 9, wherein Xis selected from hydrogen, deuterium, fluorine, bromine, iodine, methyl,ethyl, vinyl, and ethynyl, and wherein R₉ is selected from hydrogen,deuterium, fluorine, bromine, iodine, methyl and ethyl.
 11. The compoundof formula (I-1), the stereoisomer, tautomer or pharmaceuticallyacceptable salt thereof according to claim 9, which is one of thefollowing compounds, stereoisomers, tautomers or pharmaceuticallyacceptable salts thereof,

.
 12. A pharmaceutical composition comprising a therapeuticallyeffective dose of the compound of claim 1 or a stereoisomer, tautomer orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 13. A method for the treatment and improvement ofdiabetes, cardiovascular and cerebrovascular diseases, weight loss,fatty liver, constipation, metabolism-related diseases or for thetreatment of tumors, comprising administering the compound according toclaim 1 or a pharmaceutically acceptable salt thereof or thepharmaceutical composition thereof.
 14. A method for the treatment ofdiseases related to SGLT1/SGLT2 function, comprising administering thecompound according to claim 1 or a pharmaceutically acceptable saltthereof or the pharmaceutical composition thereof, as SGLT1/SGLT2inhibitor.
 15. The method according to claim 13, wherein the patient hastaken or is currently taking other therapeutic drugs, includinghypotensive drugs, hypolipidemic drugs, antidiabetic drugs, hypoglycemicdrugs, weight-loss drugs or appetite suppressants.
 16. A pharmaceuticalcomposition comprising a therapeutically effective dose of the compoundof claim 6 or a stereoisomer, tautomer or pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier.
 18. A method forthe treatment and improvement of diabetes, cardiovascular andcerebrovascular diseases, weight loss, fatty liver, constipation,metabolism-related diseases or for the treatment of tumors, comprisingadministering the compound according to claim 6 or a pharmaceuticallyacceptable salt thereof or the pharmaceutical composition thereof.
 19. Amethod for the treatment of diseases related to SGLT1/SGLT2 function,comprising administering the compound according to claim 6 or apharmaceutically acceptable salt thereof or the pharmaceuticalcomposition thereof, as SGLT1/SGLT2 inhibitor.